jci.org/impactjanuary 2015

Also in this issue:

β Cell preservation in type 1 diabetes 7

Blood pressure circadian rhythms 8

DNA damage in autoimmunity 9

Review series: Autophagy edited by Guido Kroemer 10

A summary of this month’s Journal of Clinical investigation

tAlens forcervical cancer p. 6

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The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.

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Impactjanuary 2015

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anna Mae Diehl, M.D., associate Editor, is the Florence McAlister Professor of Medicine and Professor in Molecular Genetics and Microbiology, and Director of the Liver Center at Duke University School of Medicine. She also directs the Duke Gastroenterology Division T32 Research Training Program. Her research programs encompass patient-based clinical research on fatty liver diseases and liver fibrosis, as well as more basic translational work that focuses on liver regeneration. Dr. Diehl is a member of the American Association for the Study of Liver Diseases (AASLD), the American Society for Clinical Investigation, and the Association of American Physicians. She has served on the

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Yang L, Jung Y, Omenetti A, Witek RP, Choi S, Vandongen HM, Huang J, Alpini G, Diehl AM. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells. 2008;26(8):2104–2113.

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Research articles in the current issue of the JCI

Cardiac channelopathy

CardiologyGenetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmiasDavid S. Park, Marina Cerrone, Gregory Morley, Carolina Vasquez, Steven Fowler, Nian Liu, Scott A. Bernstein, Fang-Yu Liu, Jie Zhang, Christopher S. Rogers, Silvia G. Priori, Larry A. Chinitz, and Glenn I. Fishman http://jci.me/76919

With related Commentary by arthur a.M. Wilde and Pieter G. Postema

More, p. 7

Clinical trialsClinical trial demonstrates exercise following bariatric surgery improves insulin sensitivityPaul M. Coen, Charles J. Tanner, Nicole L. Helbling, Gabriel S. Dubis, Kazanna C. Hames, Hui Xie, George M. Eid, Maja Stefanovic-Racic, Frederico G.S. Toledo, John M. Jakicic, Joseph A. Houmard, and Bret H. Goodpaster http://jci.me/78016

antithymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetesMichael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Stephen M. Rosenthal, Jonathan J. Shuster, Baiming Zou, Todd M. Brusko, Maigan A. Hulme, Clive H. Wasserfall, Clayton E. Mathews, Mark A. Atkinson, and Desmond A. Schatz http://jci.me/78492

With related Commentary by jay S. Skyler

More, p. 7

EndocrinologyTargeting development of incretin-producing cells increases insulin secretionNatalia Petersen, Frank Reimann, Johan H. van Es, Bernard M. van den Berg, Chantal Kroone, Ramona Pais, Erik Jansen, Hans Clevers, Fiona M. Gribble, and Eelco J.P. de Koning http://jci.me/75838

Glucokinase activity in the arcuate nucleus regulates glucose intakeSyed Hussain, Errol Richardson, Yue Ma, Christopher Holton, Ivan De Backer, Niki Buckley, Waljit Dhillo, Gavin Bewick, Shuai Zhang, David Carling, Steve Bloom, and James Gardiner http://jci.me/77172

GeneticsExome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instabilitySaleh AlAsiri, Sulman Basit, Michelle A. Wood-Trageser, Svetlana A. Yatsenko, Elizabeth P. Jeffries, Urvashi Surti, Deborah M. Ketterer, Sibtain Afzal, Khushnooda Ramzan, Muhammad Faiyaz-Ul Haque, Huaiyang Jiang, Michael A. Trakselis, and Aleksandar Rajkovic http://jci.me/78473

Intestinal L cells

MCM8 mutant nuclei

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Research articles in the current issue of the JCI

HematologySumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factorKlaus-Dieter Preuss, Michael Pfreundschuh, Natalie Fadle, Evi Regitz, and Boris Kubuschok http://jci.me/76802

Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacityMamle Quarmyne, Phuong L. Doan, Heather A. Himburg, Xiao Yan, Mai Nakamura, Liman Zhao, Nelson J. Chao, and John P. Chute http://jci.me/77866

HepatologyIntestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver diseaseChangtao Jiang, Cen Xie, Fei Li, Limin Zhang, Robert G. Nichols, Kristopher W. Krausz, Jingwei Cai, Yunpeng Qi, Zhong-Ze Fang, Shogo Takahashi, Naoki Tanaka, Dhimant Desai, Shantu G. Amin, Istvan Albert, Andrew D. Patterson, and Frank J. Gonzalez http://jci.me/76738

Hepatic TraP80 selectively regulates lipogenic activity of liver X receptorGeun Hyang Kim, Gyun-Sik Oh, Jin Yoon, Gang Gu Lee, Ki-Up Lee, and Seung-Whan Kim http://jci.me/73615

More, p. 9

ImmunologyDefective removal of ribonucleotides from Dna promotes systemic autoimmunityClaudia Günther, Barbara Kind, Martin A.M. Reijns, Nicole Berndt, Manuel Martinez-Bueno, Christine Wolf, Victoria Tüngler, Osvaldo Chara, Young Ae Lee, Norbert Hübner, Louise Bicknell, Sophia Blum, Claudia Krug, Franziska Schmidt, Stefanie Kretschmer, Sarah Koss, Katy R. Astell, Georgia Ramantani, Anja Bauerfeind, David L. Morris, Deborah S. Cunninghame Graham, Doryen Bubeck, Andrea Leitch, Stuart H. Ralston, Elizabeth A. Blackburn, Manfred Gahr, Torsten Witte, Timothy J. Vyse, Inga Melchers, Elisabeth Mangold,

Markus M. Nöthen, Martin Aringer, Annegret Kuhn, Kirsten Lüthke, Leonore Unger, Annette Bley, Alice Lorenzi, John D. Isaacs, Dimitra Alexopoulou, Karsten Conrad, Andreas Dahl, Axel Roers, Marta E. Alarcon-Riquelme, Andrew P. Jackson, and Min Ae Lee-Kirsch http://jci.me/78001

With related Commentary by William F. Pendergraft III and Terry K. Means

More, p. 9

Podoplanin negatively regulates CD4+ effector T cell responsesAnneli Peters, Patrick R. Burkett, Raymond A. Sobel, Christopher D. Buckley, Steve P. Watson, Estelle Bettelli, and Vijay K. Kuchroo http://jci.me/74685

Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLaHiroko Miyadera, Jun Ohashi, Åke Lernmark, Toshio Kitamura, and Katsushi Tokunaga http://jci.me/74961

Survivin-specific T cell receptor targets tumor but not T cellsCaroline Arber, Xiang Feng, Harshal Abhyankar, Errika Romero, Meng-Fen Wu, Helen E. Heslop, Patrick Barth, Gianpietro Dotti, and Barbara Savoldo http://jci.me/75876

Follicular helper T cell signature in type 1 diabetesRupert Kenefeck, Chun Jing Wang, Tauseef Kapadi, Lukasz Wardzinski, Kesley Attridge, Louise E. Clough, Frank Heuts, Alexandros Kogimtzis, Sapna Patel, Miranda Rosenthal, Masahiro Ono, David M. Sansom, Parth Narendran, and Lucy S.K. Walker http://jci.me/76238

Liver fat accumulation

Lupus skin lesions

Pancreatic T cells

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Research articles in the current issue of the JCI

ImmunologyMetabolic programming and PDHK1 control CD4+ T cell subsets and inflammationValerie A. Gerriets, Rigel J. Kishton, Amanda G. Nichols, Andrew N. Macintyre, Makoto Inoue, Olga Ilkayeva, Peter S. Winter, Xiaojing Liu, Bhavana Priyadharshini, Marta E. Slawinska, Lea Haeberli, Catherine Huck, Laurence A. Turka, Kris C. Wood, Laura P. Hale, Paul A. Smith, Martin A. Schneider, Nancie J. MacIver, Jason W. Locasale, Christopher B. Newgard, Mari L. Shinohara, and Jeffrey C. Rathmell http://jci.me/76012

NephrologyIntronic locus determines SHROOM3 expression and potentiates renal allograft fibrosisMadhav C. Menon, Peter Y. Chuang, Zhengzhe Li, Chengguo Wei, Weijia Zhang, Yi Luan, Zhengzi Yi, Huabao Xiong, Christopher Woytovich, Ilana Greene, Jessica Overbey, Ivy Rosales, Emilia Bagiella, Rong Chen, Meng Ma, Li Li, Wei Ding, Arjang Djamali, Millagros Saminego, Philip J. O’Connell, Lorenzo Gallon, Robert Colvin, Bernd Schroppel, John Cijiang He, and Barbara Murphy http://jci.me/76902

mTOrC2 regulates renal tubule sodium uptake by promoting EnaC activityCatherine E. Gleason, Gustavo Frindt, Chih-Jen Cheng, Michael Ng, Atif Kidwai, Priyanka Rashmi, Florian Lang, Michael Baum, Lawrence G. Palmer, and David Pearce http://jci.me/73935

anti–microrna-21 oligonucleotides prevent alport nephropathy progression by stimulating metabolic pathwaysIvan G. Gomez, Deidre A. MacKenna, Bryce G. Johnson, Vivek Kaimal, Allie M. Roach, Shuyu Ren, Naoki Nakagawa, Cuiyan Xin, Rick Newitt, Shweta Panya, Tai-He Xia, Xueqing Liu, Dorin-Bogdan Borza, Monica Grafals, Stuart J. Shankland, Jonathan Himmelfarb, Didier Portilla, Shiguang Liu, B. Nelson Chau, and Jeremy S. Duffield http://jci.me/75852

NeuroscienceLong-term potentiation decay and memory loss are mediated by aMPar endocytosisZhifang Dong, Huili Han, Hongjie Li, Yanrui Bai, Wei Wang, Man Tu, Yan Peng, Limin Zhou, Wenting He, Xiaobin Wu, Tao Tan, Mingjing Liu, Xiaoyan Wu, Weihui Zhou, Wuyang Jin, Shu Zhang, Todd Charlton Sacktor, Tingyu Li, Weihong Song, and Yu Tian Wang http://jci.me/77888

CXCr3 promotes plaque formation and behavioral deficits in an alzheimer’s disease modelMarius Krauthausen, Markus P. Kummer, Julian Zimmermann, Elisabet Reyes-Irisarri, Dick Terwel, Bruno Bulic, Michael T. Heneka, and Marcus Müller http://jci.me/66771

Prostaglandin signaling suppresses beneficial microglial function in alzheimer’s disease modelsJenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, and Katrin I. Andreasson http://jci.me/77487

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCa28 modelFrancesca Maltecca, Elisa Baseggio, Francesco Consolato, Davide Mazza, Paola Podini, Samuel M. Young Jr., Ilaria Drago, Ben A. Bahr, Aldamaria Puliti, Franca Codazzi, Angelo Quattrini, and Giorgio Casari http://jci.me/74770

More, p. 8

Renal allograft fibrosis

Ceftriaxone-treated cerebellum

Hippocampal necrotic plaques

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Research articles in the current issue of the JCI

OncologyLMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesisShi-Dong Ma, Xuequn Xu, Julie Plowshay, Erik A. Ranheim, William J. Burlingham, Jeffrey L. Jensen, Fotis Asimakopoulos, Weihua Tang, Margaret L. Gulley, Ethel Cesarman, Jenny E. Gumperz, and Shannon C. Kenney http://jci.me/76357

rare codons capacitate Kras-driven de novo tumorigenesisNicole L.K. Pershing, Benjamin L. Lampson, Jason A. Belsky, Erin Kaltenbrun, David M. MacAlpine, and Christopher M. Counter http://jci.me/77627

More, p. 8

TaLEn-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancyZheng Hu, Wencheng Ding, Da Zhu, Lan Yu, Xiaohui Jiang, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Dan Liu, Dan He, Xi Xia, Tao Zhu, Juncheng Wei, Peng Wu, Changyu Wang, Ling Xi, Qinglei Gao, Gang Chen, Rong Liu, Kezhen Li, Shuang Li, Shixuan Wang, Jianfeng Zhou, Ding Ma, and Hui Wang http://jci.me/78206

More, p. 6

OphthalmologyViral-mediated rdCVF and rdCVFL expression protects cone and rod photoreceptors in retinal degenerationLeah C. Byrne, Deniz Dalkara, Gabriel Luna, Steven K. Fisher, Emmanuelle Clérin, Jose-Alain Sahel, Thierry Léveillard, and John G. Flannery http://jci.me/65654

Vascular biologySmooth-muscle BMaL1 participates in blood pressure circadian rhythm regulationZhongwen Xie, Wen Su, Shu Liu, Guogang Zhao, Karyn Esser, Elizabeth A. Schroder, Mellani Lefta, Harald M. Stauss, Zhenheng Guo, and Ming Cui Gong http://jci.me/76881

More, p. 8

VirologyHuman pDCs preferentially sense enveloped hepatitis a virionsZongdi Feng, You Li, Kevin L. McKnight, Lucinda Hensley, Robert E. Lanford, Christopher M. Walker, and Stanley M. Lemon http://jci.me/77527

naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistanceJustin R. Bailey, Lisa N. Wasilewski, Anna E. Snider, Ramy El-Diwany, William O. Osburn, Zhenyong Keck, Steven K.H. Foung, and Stuart C. Ray http://jci.me/78794

With related Commentary by jay K. Kolls and Gyongyi Szabo

More, p. 9

T cell–infiltrated lymphoma

Hepatitis A virus in liver

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HPV encompasses a family of more than 100 different viruses. Though many HPV infections do not induce any symptoms, some types of the virus are responsible for causing warts, sexually transmitted infections, and cancers, such as cervical cancer. Nearly all cases of cervical cancer are associated with HPV infection, and two virally encoded proteins, known as E6 and E7, are responsible for degrading the tumor suppressors p53 and retinoblastoma (RB). In this month’s issue of the JCI, Zheng Hu and colleagues report the development of a new strategy to target HPV-infected cells using a topical application of transcription activator–like effector nucle-ases (TALENs). The research team designed TALENs, which are targeted nucleases that can edit the genome at specific DNA sequences, to block expression of the HPV oncogenes E6 and E7. In cultured cells with HPV infec-tion, the TALENs restored expression of p53 and RB, leading to growth inhibition and apoptosis of infected cells. Further, using a mouse model of cervical cancer, the researchers showed that the application of polymer-complexed TALENs directly to the cervix reduced viral DNA load, triggered reexpression of RB, and reversed the malignant phenotype of infected cells. Cumulatively, their work provides compelling evidence that a TALEN-based approach can be used to target viral infections and offers a new therapeutic avenue for treating HPV-related diseases. The accompanying image shows immuno-histo chemical staining of CD45 (brown) with hema-toxylin (blue) counterstain in mechanically stretched FVB mouse cervical tissue to examine the inflammatory response in TALEN-treated mice.

TaLEn-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancyZheng Hu, Wencheng Ding, Da Zhu, Lan Yu, Xiaohui Jiang, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Dan Liu, Dan He, Xi Xia, Tao Zhu, Juncheng Wei, Peng Wu, Changyu Wang, Ling Xi, Qinglei Gao, Gang Chen, Rong Liu, Kezhen Li, Shuang Li, Shixuan Wang, Jianfeng Zhou, Ding Ma, and Hui Wang http://jci.me/78206

A genome-editing approach to target HPV-infected cells

Editor’s picksresearch

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Research | Editor’s Picks

cardiology

A porcine model of cardiac sodium channelopathy

Progressive cardiac conduction disorders and arrhythmic conditions, such as Brugada syndrome, are caused by electrophysiological defects, some of which have been linked to loss-of-function mutations in the sodium channel–encoding gene SCN5A. David Park and colleagues developed a pig model expressing an early truncation mutant of SCN5A that was originally identified in a child with Brugada syndrome. Pigs expressing the orthologous mutation, SCN5AE558X, had reduced expression of the sodium channel and exhibited conduction abnormalities, but did not have any cardiac structural defects. Electrophysiological analyses showed that mutant pigs had slow conduction, enhanced sensitivity to sodium channel blockers, and increased susceptibility to ventricular fibrillation (see the accompanying image). In the accompanying Commentary, Arthur Wilde and Pieter Postema discuss how this model could potentially be used to gain insight into the role of sodium channel dysfunction in cardiac arrhythmias.

Immunomodulatory agents preserve β cells in patients with type 1 diabetestype i diabetes (t1D) is caused by the autoimmune-mediated destruction of pancreatic β cells, which could potentially be ameliorated through treatment with immunomodulatory drugs. Thus far, no single agent trial has demonstrated long-term preservation of β cell function; however, a combination of immunomodulatory agents could have potentially synergistic effects. In this issue, Michael Haller and colleagues reported on the results of a randomized, single-blinded clinical trial in 25 patients with established T1D that compared treatment with a combination of antithymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) to that with placebo. β Cell function was assessed prior to the beginning of and 1 year after treatment by measuring C-peptide levels following a mixed-meal tolerance test. Haller and colleagues found that 9 of 16 patients treated with ATG/G-CSF had C-peptide levels at or above their baseline value,

while patients receiving placebo exhibited a 40% decline in C-peptide. These results indicate that ATG/G-CSF treatment tended to preserve β cell function. In the accompanying Commentary, Jay Skyler discusses how these results support further clinical investigation of combinatorial immunomodulatory therapy in T1D.

antithymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetesMichael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Stephen M. Rosenthal, Jonathan J. Shuster, Baiming Zou, Todd M. Brusko, Maigan A. Hulme, Clive H. Wasserfall, Clayton E. Mathews, Mark A. Atkinson, and Desmond A. Schatz http://jci.me/78492

related CommentaryImmune therapy for treating type 1 diabetes: challenging existing paradigmsJay S. Skyler http://jci.me/79190

clinical trials

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmiasDavid S. Park, Marina Cerrone, Gregory Morley, Carolina Vasquez, Steven Fowler, Nian Liu, Scott A. Bernstein, Fang-Yu Liu, Jie Zhang, Christopher S. Rogers, Silvia G. Priori, Larry A. Chinitz, and Glenn I. Fishman http://jci.me/76919

related CommentaryBringing home the bacon? The next step in cardiac sodium channelopathiesArthur A.M. Wilde and Pieter G. Postema http://jci.me/80014

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Research | Editor’s Picks

Glutamate inhibition ameliorates spinocerebellar ataxia type 28 in mice

neuroscience

spinocerebellar ataxia type 28 (sCA28) is caused by mutations in the mitochondrial protease–encoding gene AFG3L2. An Afgl3l2-haploinsufficient mouse (Afgl3l2+/–) exhibits ataxia and degeneration of Purkinje cells, which are characteristic of the disease. Francesca Maltecca and colleagues showed that Afgl3l2 depletion in cultured murine Purkinje cells caused impaired mitochondrial calcium buffering and increased cytoplasmic calcium, which triggered degeneration and cell death (see accompanying image). Reduced expression of the metabotropic glutamate receptor mGluR1, which mediates calcium influx, reversed Purkinje cell degeneration and ataxia in Afgl3l2+/– mice. Moreover, treatment with the antibiotic ceftriaxone, which increases expression of the astrocyte glutamate transporter EAAT2, decreased glutamatergic stimulation and subsequent calcium influx to ameliorate the murine SCA28 phenotype.

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCa28 modelFrancesca Maltecca, Elisa Baseggio, Francesco Consolato, Davide Mazza, Paola Podini, Samuel M. Young Jr., Ilaria Drago, Ben A. Bahr, Aldamaria Puliti, Franca Codazzi, Angelo Quattrini, and Giorgio Casari http://jci.me/74770

vascular biology

Cracking the codon bias of KRAS in tumorigenesisVascular smooth-muscle clock

gene mediates blood pressure circadian rhythmhuman blood pressure exhibits daily oscillations that correspond to circadian rhythms, with pressure falling at night and rising in the morning. Importantly, the morning blood pressure increase is associated with a greater risk of stroke and sudden cardiac death. Zhongwen Xie, Wen Su, and colleagues demonstrate that specific deletion of the clock gene Bmal1 in vascular smooth muscle, but not cardiomyocytes, disrupts circadian blood pressure oscillations and decreases blood pressure in mice. Mechanistically, BMAL1 bound and activated the Rho-kinase 2 (Rock2) promoter in mesenteric arteries to induce vasoconstriction. These data elucidate a molecular mechanism that controls blood pressure circadian rhythms.

Smooth-muscle BMaL1 participates in blood pressure circadian rhythm regulationZhongwen Xie, Wen Su, Shu Liu, Guogang Zhao, Karyn Esser, Elizabeth A. Schroder, Mellani Lefta, Harald M. Stauss, Zhenheng Guo, and Ming Cui Gong http://jci.me/76881

oncology

KRAS is commonly mutated in human cancers; however, KRAS can activate both tumorigenic and cellular senescence pathways. The outcome of KRAS signaling appears to be largely determined by protein expression levels, with high levels of KRAS inducing senescence and low levels inducing hyperplasia. KRAS is preferentially encoded by rare codons, which limit protein expression. In order to assess the functional implications of rare codon bias in tumorigenesis, Nicole Pershing and colleagues created a knock-in mouse expressing a Kras allele in which the rare codons in exon 3 were converted into common codons (Krasex3op). Mice expressing Krasex3op had increased KRAS expression, reduced tumor burden, decreased tumor initiation following carcinogen exposure, and fewer oncogenic mutations compared with mice expressing WT Kras. Moreover, introduction of a common oncogenic mutation in Krasex3op induced growth arrest instead of transformation in normal cells. These data demonstrate that rare codon bias in Kras has functional consequences during tumorigenesis.

rare codons capacitate Kras-driven de novo tumorigenesisNicole L.K. Pershing, Benjamin L. Lampson, Jason A. Belsky, Erin Kaltenbrun, David M. MacAlpine, and Christopher M. Counter http://jci.me/77627

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Research | Editor’s Picks

Mapping neutralizing antibody resistance in “wild” hepatitis C virus variants

virology

Chronic low-level DNA damage promotes systemic autoimmunityAicardi-Goutières syndrome (AGs) is a pediatric-onset inflammatory disorder that shares features with systemic lupus erythematosus (SLE). The disease is caused by biallelic mutations in genes encoding the ribonuclease H2 (RNase H2) complex, which is required for the maintenance of genome integrity. Min Ae Lee-Kirsch and colleagues demonstrate that rare genetic variants in the genes encoding RNase H2 are associated with systemic autoimmunity, including the presence of autoantibodies. Sequencing of SLE patients and healthy controls revealed that RNase H2 variants resulting in impaired enzyme function were associated with SLE. Such mutations impaired ribonucleotide removal from genomic DNA, leading to genomic instability in both AGS and SLE patient fibroblasts. The resulting chronic low-level DNA damage triggered a DNA damage response characterized by increased p53 signaling and senescence. Patient fibroblasts also had an enhanced type I IFN response to UV-induced pyrimidine dimer formation. In the accompanying Commentary, William Pendergraft and Terry Means discuss how these findings link RNase H2 dysfunction to systemic autoimmunity.

Defective removal of ribonucleotides from Dna promotes systemic autoimmunityClaudia Günther, Barbara Kind, Martin A.M. Reijns, Nicole Berndt, Manuel Martinez-Bueno, Christine Wolf, Victoria Tüngler, Osvaldo Chara, Young Ae Lee, Norbert Hübner, Louise Bicknell, Sophia Blum, Claudia Krug, Franziska Schmidt, Stefanie Kretschmer, Sarah Koss, Katy R. Astell, Georgia Ramantani, Anja Bauerfeind, David L. Morris, Deborah S. Cunninghame Graham, Doryen Bubeck, Andrea Leitch, Stuart H. Ralston, Elizabeth A. Blackburn, Manfred Gahr, Torsten Witte, Timothy J. Vyse, Inga Melchers, Elisabeth Mangold, Markus M. Nöthen, Martin Aringer, Annegret Kuhn, Kirsten Lüthke, Leonore Unger, Annette Bley, Alice Lorenzi, John D. Isaacs, Dimitra Alexopoulou, Karsten Conrad, Andreas Dahl, Axel Roers, Marta E. Alarcon-Riquelme, Andrew P. Jackson, and Min Ae Lee-Kirsch http://jci.me/78001

related CommentaryaGS, SLE, and RNASEH2 mutations: translating insights into therapeutic advancesWilliam F. Pendergraft III and Terry K. Means http://jci.me/78533

immunology

efforts to develop a hepatitis C virus (hCV) vaccine have been stymied by the broad genetic diversity of the virus and its rapid evolution in infected individuals. Patients develop broadly neutralizing mAbs that target the HCV envelopes (E1E2); however, the virus eventually becomes resistant to these antibodies. To gain a better understanding of HCV resistance mechanisms, Justin Bailey and colleagues created a panel of clones that contains 94% of amino acid polymorphisms present at greater than 5% frequency in 643 isolates from patients with genotype 1 HCV. They then tested neutralization breadth of 18 previously described, broadly neutralizing anti-HCV human mAbs. They identified E1E2 polymorphisms that were associated with broad resistance, and, strikingly, many of these polymorphisms were located in a region of E2 that is distinct from antibody-binding sites. In the accompanying Commentary, Jay Kolls and Gyongyi Szabo discuss how these data reveal mechanisms of resistance that could inform rational design of an HCV vaccine.

naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistanceJustin R. Bailey, Lisa N. Wasilewski, Anna E. Snider, Ramy El-Diwany, William O. Osburn, Zhenyong Keck, Steven K.H. Foung, and Stuart C. Ray http://jci.me/78794

related CommentaryThe genetics of hepatitis C virus underlie its ability to escape humoral immunityJay K. Kolls and Gyongyi Szabo http://jci.me/79424

“TRAP-ing” liver X receptor effects on triglyceride biosynthesisthe liver X receptor (lXR) is a nuclear hormone receptor that mediates opposing effects on lipid homeostasis; LXR stimulates reverse cholesterol transport (RCT) by enhancing expression of ATP–binding cassette A1 (ABCA1), but promotes hepatic triglyceride synthesis by enhancing expression of sterol regulatory element–binding protein-1c (SREBP-1c). Seung-Whan Kim and colleagues report that the LXR coactivator thyroid hormone receptor–associated protein 80 (TRAP80) selectively promotes expression of SREBP-1c. Liver-specific knockdown of Trap80 in mice ameliorated LXR-induced hepatosteatosis and hypertriglyceridemia (see accompanying image), but did not alter RCT. These findings indicate that inhibition of LXR/TRAP80 interaction could be exploited to promote RCT to reduce cholesterol and potentially treat cholesterol-related diseases.

Hepatic TraP80 selectively regulates lipogenic activity of liver X receptorGeun Hyang Kim, Gyun-Sik Oh, Jin Yoon, Gang Gu Lee, Ki-Up Lee, and Seung-Whan Kim http://jci.me/73615

hepatology

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review Series

Autophagy

The term autophagy, or “self-eating,” refers to the processes by which cells deliver cyto-plasmic constituents to lysosomes for degradation. Autophagy provides biosynthetic precursors and energy sources to sustain metabolism and cell growth and prevent the accumulation of toxic components. These processes are invoked in response to stressors, including changing nutrient conditions, damage to organelles, intracellular pathogens, and accumulation of reactive oxygen species, among others, in order to maintain cel-lular homeostasis. Autophagy becomes insufficient with age and is perturbed in multiple disease states, including cardiovascular disease, cancer, immune-related diseases, and neurodegeneration. Series Editor Guido Kroemer discusses how pathogenic aberrations in autophagy have emerged as a major focus in the development of novel therapeutic strate-gies. Human genetic studies have identified multiple polymorphisms in autophagy-related genes that are linked to specific disease states. Careful dissection of cellular autophagy pathways have revealed new targets for the development of autophagy inducers, which are being tested in preclinical models and are beginning to enter human clinical trials.

autophagy: a druggable process that is deregulated in aging and human diseaseGuido Kroemer http://jci.me/78652

Guido Kroemer, MD, PhD, is a Professor of the Faculty of Medicine of the University of Paris Descartes, Director of Research Unit 848, “Apoptosis, Cancer, and Immunity,” of the French Medical Research Council (INSERM), Director of the Metabolomics Facility of the Institut Gustave Roussy, and a Hospital Practitioner at the Hôpital Européen Georges-Pompidou, Paris, France. His research focuses on autophagy as a cytoprotective mechanism, the mechanisms of mitochondrial cell death control, the molecular pathways that inhibit cell death in cancer cells, and the mechanisms that make cancer cell death immunogenic.

An expanding role for autophagy in physiology and diseaseSeries Editor: Guido Kroemer

Pharmacologic agents targeting autophagyHelin Vakifahmetoglu-Norberg, Hong-guang Xia, and Junying Yuan

Development of autophagy inducers in clinical medicineBeth Levine, Milton Packer, and Patrice Codogno

mTOr: a pharmacologic target for autophagy regulationYoung Chul Kim and Kun-Liang Guan

The functional and pathologic relevance of autophagy proteasesÁlvaro F. Fernández and Carlos López-Otín

The role for autophagy in cancerEileen White

autophagy in cellular metabolism and cancerXuejun Jiang, Michael Overholtzer, and Craig B. Thompson

autophagy in cardiovascular biologySergio Lavandero, Mario Chiong, Beverly A. Rothermel, and Joseph A. Hill

autophagy and neurodegenerationRebecca A. Frake, Thomas Ricketts, Fiona M. Menzies, and David C. Rubinsztein

Immunologic manifestations of autophagyVojo Deretic, Tomonori Kimura, Graham Timmins, Pope Moseley, Santosh Chauhan, and Michael Mandell

Essential role for autophagy in life span extensionFrank Madeo, Andreas Zimmermann, Maria Chiara Maiuri, and Guido Kroemer

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Review Series | Autophagy

Tools for studying and targeting autophagyMutations in the autophagic machinery and its associated components have been linked to a number of human diseases. Because of the pathophysiologic significance of autophagy, numerous screening tools and small molecules have been developed to aid in the dissection of the relevant pathways and to potentially be used as therapeutics. In this Review, Junying Yuan and colleagues discuss currently available small molecules and other pharmacologic agents that target regulatory mechanisms of autophagy, as well as screening strategies for the identification of autophagy regulators. The accompanying image details compounds that target different points in the autophagic pathway.

Pharmacologic agents targeting autophagyHelin Vakifahmetoglu-Norberg, Hong-guang Xia, and Junying Yuan http://jci.me/73937

Targeting mTOR to modulate autophagymtoR is a nutrient-sensing kinase that serves as the catalytic subunit of two distinct complexes, mTORC1 and mTORC2, which regulate cellular growth and metabolism. When nutrients are plentiful, mTOR promotes anabolic metabolism and cell growth and inhibits autophagy. When nutrients are in short supply and cellular energy stores are low, mTOR is inhibited and autophagy is activated to recycle cellular components, thereby generating energy and recovering precursors that are required for cellular growth. In this Review, Young Chul Kim and Kun-Liang Guan provided an overview of the mTOR signaling pathway, detailed the dynamic signaling interplay between mTOR and autophagy, and discussed the impact of pharmacological inhibitors of mTOR, such as rapamycin, in autophagy-related diseases.

mTOr: a pharmacologic target for autophagy regulationYoung Chul Kim and Kun-Liang Guan http://jci.me/73939

Autophagy in innate and adaptive immunityAutophagy, which functions to eliminate cytoplasmic constituents, may be one of the earliest forms of eukaryotic innate defense against microorganisms. In this Review, Vojo Deretic and colleagues examine the roles of autophagy in innate and adaptive immunity. Autophagy influences the development, repertoire selection, maturation, homeostasis, and function of immune cells (see accompanying image; red crescents indicate a role for autophagy). Inflammatory responses are also regulated by autophagy, and multiple genetic polymorphisms link autophagy to inflammatory disorders, such as Crohn’s disease and rheumatoid arthritis. Deretic and colleagues examined the role of autophagy in Mycobacterium tuberculosis infection

as a paradigm for immunological manifestations of autophagy. They detailed the role of autophagy-mediated intracellular pathogen elimination and inflammatory responses as well as autophagy-mediated modulation of systemic inflammation and the ability of M. tuberculosis to deploy countermeasures against autophagy.

Immunologic manifestations of autophagyVojo Deretic, Tomonori Kimura, Graham Timmins, Pope Moseley, Santosh Chauhan, and Michael Mandell http://jci.me/73945

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Review Series | Autophagy

Exploring autophagy in the cardiovascular systemAlterations in nutrients, oxygen levels, energy status, or external stresses can contribute to changes in cardiovascular function. Autophagy is now known to serve as a compensatory mechanism in heart and vascular tissues. Joseph Hill and colleagues review the evidence for a role of autophagy in cardiovascular disease. Although autophagy is frequently protective and required for normal maintenance, repair, and adaptation, excessive or insufficient autophagy can cause cell death in cardiovascular tissues. Evidence of autophagy in human heart disease was first reported in tissue samples from patients with dilated cardiomyopathy, and it has since been linked to heart failure, ischemia/reperfusion injury, cardiomyopathies, atrial fibrillation, atherosclerosis, and vascular remodeling.

autophagy in cardiovascular biologySergio Lavandero, Mario Chiong, Beverly A. Rothermel, and Joseph A. Hill http://jci.me/73943

Moving autophagy modulators from bench to bedsideAutophagy plays a role in protection against certain cancers, infections, neuro-degenerative disorders, metabolic diseases, inflammation, and muscle diseases. A common pathological event in these diseases is the accumulation of harmful contents inside the cell; however, autophagy is impaired in a variety of ways. Beth Levine and colleagues summarize the rationale and current approaches for developing autophagy inducers for clinical use. Autophagy occurs in every tissue, and the specificity, tolerability, and safety of autophagy-targeted therapeutics are not known. Challenges include measuring autophagic flux in humans and defining the relationship between autophagy and disease-specific outcomes. Therapeutic advances will require the development of screening techniques that monitor not only autophagy induction, but also substrate clearance.

Development of autophagy inducers in clinical medicineBeth Levine, Milton Packer, and Patrice Codogno http://jci.me/73938

the essential function of autophagy is the degradation of cellular components. Components marked for degradation are first isolated in a double-membrane structure known as the autophagosome, which eventually fuses with a lysosome. The ATG4 cysteine proteases, also known as autophagins, participate in the formation, elongation, and lysosomal fusion of the autophagosome. Notably, dysregulation of these cysteine proteases is associated with several human pathologies, pointing to their potential as therapeutic targets. Álvaro Fernández and Carlos López-Otín review the identification of the four mammalian homologs of the yeast protease ATG4, their role in autophagosome formation, their substrate and pathway specificity (see accompanying image), and potential therapeutics based on the modulation of ATG4 cysteine proteases.

The functional and pathologic relevance of autophagy proteasesÁlvaro F. Fernández and Carlos López-Otín http://jci.me/73940

a D V E r T I S E M E n T

A central role for ATG4/autophagins in autophagosome formation

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Review Series | Autophagy

a D V E r T I S E M E n T

Context-dependent roles for autophagy in oncogenesisAutophagy is primarily a survival-promoting pathway that helps cells endure environmental stress. Importantly, cancer cells can modulate autophagy to increase growth and aggressiveness. Eileen White reviews the evidence for tumor suppressor and tumor promoter functions of autophagy in different genetically engineered mouse models of cancer. Autophagy inhibits oxidative stress, inflammation, and DNA damage, thereby preventing oncogenesis. However, autophagy is frequently upregulated in RAS- or BRAF-driven cancers, in which loss of autophagy mediators results in accumulation of defective mitochondria, proliferative defects, reduced tumor burden, and increased survival. Future studies will need to examine the expression of autophagy genes in human cancers and identify autophagy substrates involved in survival and proliferation.

The role for autophagy in cancerEileen White http://jci.me/73941

Autophagy as an anti-aging mechanismAged cells are characterized by accumulation of molecular damage, including malfunctioning organelles, protein aggregates, defective enzymes, or DNA mutations. Such defects also characterize age-associated diseases, such as neurodegeneration and cancer. Frank Madeo, Guido Kroemer, and colleagues discuss recent evidence indicating that increased autophagic flux extends life and/or health span. The life span of model organisms such as D. melanogaster or C. elegans can be extended through various pharmacologic or genetic manipulations; however, these manipulations fail if autophagy is inactivated. Furthermore, autophagy induction is sufficient to promote longevity. Autophagy mediates these life span–extending effects through clearance of damaged proteins and organelles, improvement of organismal lipid profiles, hormesis, and protection against oncogenesis and inflammation.

Essential role for autophagy in life span extensionFrank Madeo, Andreas Zimmermann, Maria Chiara Maiuri, and Guido Kroemer http://jci.me/73946

Autophagy and nutrient signaling in cancer metabolismAutophagy is a catabolic process that is crucial to the maintenance of cellular viability and homeostasis. Xuejun Jiang, Michael Overholtzer, and Craig Thompson examine the role of autophagy in nutrient signaling in normal and cancerous cells. The ULK1 complex plays an essential role in autophagy initiation, receiving information about cellular nutrient/energy status from AMPK and mTORC1 and recruiting downstream autophagy regulatory proteins to govern autophagosome formation. Elegant feedback loops among mTORC1, AMPK, ULK1, and metabolites govern autophagic output. Additionally, nonautophagic processes utilize the autophagic machinery to mediate other lysosomal degradative processes and nutrient scavenging. The development of therapeutic autophagy modulators will require a detailed understanding of the molecular mechanisms governing these processes.

autophagy in cellular metabolism and cancerXuejun Jiang, Michael Overholtzer, and Craig B. Thompson http://jci.me/73942

Impaired autophagy promotes neurodegenerationthe majority of neurodegenerative diseases are characterized by the accumulation of intracellular protein aggregates, such as mutant huntingtin in Huntington’s disease, mutant α-synuclein in Parkinson’s disease, or amyloid-β plaques in Alzheimer’s disease. Autophagy is the primary method by which such aggregates are cleared from the cell. Additionally, many of these diseases are associated with mutations in the autophagic machinery, suggesting that impaired autophagy directly contributes to neurodegeneration. David Rubinsztein and colleagues discuss the evidence supporting a role for impaired autophagy in neurodegeneration as well as the potential of autophagy induction as a therapeutic strategy for these conditions.

autophagy and neurodegenerationRebecca A. Frake, Thomas Ricketts, Fiona M. Menzies, and David C. Rubinsztein http://jci.me/73944

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