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CELL BIOLOGY

Taking a turn into the nucleusUlrike Kutay and Petra Mühlhäusser

How soluble proteins get into the cell nucleus is known in great detail, but how membrane proteins make it into the inner nuclear membrane has long been an enigma. The two processes in fact turn out to be related.

Eukaryotic cells house their genome in a dedicated intracellular compartment — the cell nucleus. The boundary of this organelle is a double lipid bilayer termed the nuclear envelope, which consists of an outer nuclear membrane (ONM) that is continuous with the membrane system of the endoplasmic reticu-lum (ER), and an inner nuclear membrane (INM) of a different protein composition. Pro-teins of the INM play a pivotal role in genome organization. They are initially inserted into the ER, but how do they get to their final desti-nation in the INM? In this issue, Günter Blobel and colleagues (King et al., page 1003)1 address this long-standing question*. They report a receptor-mediated transport mechanism by which transmembrane proteins are targeted to the INM in yeast.

Exchange of material between the nucleus and the cytoplasm occurs through pores where the

This posits that, upon arrival, association with nuclear components tethers the proteins, retaining them in the INM3,4. But free diffu-sion along the pore membrane might well be hindered by NPC subcomplexes that surround and inhabit the pore membrane. Indeed, trans-port to the INM requires energy, so the diffu-sion–retention model might be too simplistic5. It may be that active remodelling of the NPC or a receptor-mediated mechanism is required for passage along the pore membrane.

Blobel and colleagues1 now describe how transmembrane proteins are targeted to the INM in budding yeast. The authors studied the transport of two novel INM proteins, Heh1p and Heh2p (relatives of known mammalian INM proteins), which they identified from database searches. Detailed sequence analysis of yeast and mammalian INM proteins, includ-ing Heh1/2p, revealed elements resembling the classical nuclear localization signal (NLS). These amino-acid sequences occur in a subset of soluble nuclear proteins that are imported by a transport receptor called kap-�/�1 (made of karyopherin-� and karyopherin-�1).

The identification of NLS-like sequences in INM proteins raised the intriguing idea that transport receptors for soluble proteins might also facilitate the passage of membrane pro-teins through the NPC. Indeed, this is exactly what Blobel and colleagues found. First, muta-tions in components of the RanGTPase system, which determines the direction in which pro-teins are transported, impaired Heh protein import. Second, proper INM targeting of Heh proteins specifically required kap-�/�1.

Additional experiments confirmed that the NLS-like sequence in Heh2p acts in INM targeting: it interacted directly with kap-�; it caused nuclear accumulation when attached to a protein normally found in the cytoplasm; and its mutation resulted in Heh2p mislocalization. Remarkably, Blobel and colleagues found that the targeting of Heh2p to the INM is uniquely supported by kap-�/�1, as the replacement of the Heh2p NLS with nuclear targeting signals specific for other import receptors failed to sustain correct localization. A receptor-specific path might therefore exist for funnelling INM proteins along the pore membrane, through the outer regions of the NPC.

Might such karyopherin-mediated protein sorting to the INM be conserved between yeast and higher eukaryotes? NLSs are predicted in a variety of mammalian INM proteins1, but their functional relevance has yet to be explored. Interestingly, a shortened kap-� variant, impor-tin-�-16, interacts with amino acids close to the transmembrane domain of a baculovirus-derived INM protein6. Importin-�-16 cannot associate with kap-�1, however, and the involvement of importin-�-16 in the passage of INM proteins across the NPC needs to be proved.

It remains to be seen whether all natural INM proteins rely on receptor-mediated trans-location. Analysis of an artificial protein chi-maera bearing a small nucleoplasmic domain

ONM and INM are interconnected (Fig. 1). These pores are occupied by nuclear pore com-plexes (NPCs) that act as molecular sieves and serve as gateways for the active, bidirectional transport of macromolecules. Molecules of rela-tive molecular mass (Mr) less than 40,000 can passively diffuse through the NPC. Transport of larger macromolecules depends on nuclear targeting signals that are recognized by shuttling transport receptors that facilitate passage through the central NPC channel. Although a variety of signals and receptors for soluble nuclear proteins have been identified, mechanisms governing the passage of INM proteins through the NPC have remained largely elusive.

After insertion into the membrane, INM proteins move by lateral diffusion through the lipid bilayer of the ER and ONM2. To reach the nuclear interior, they take a hairpin turn to the INM along the bend made by the pore mem-brane. The simplest explanation of their route to the INM is the diffusion–retention model.

Figure 1 | Receptor-mediated transport of proteins to the inner nuclear membrane (INM). INM proteins are initially inserted into the endoplasmic reticulum membrane. Blobel and colleagues1 show that INM proteins bearing a nuclear localization signal (gold circle) in their cytoplasmic domain are then bound by a complex of two karyopherin proteins. Karyopherin-α (triangle) recognizes the nuclear localization signal, and karyopherin-β1 (pentagon) probably mediates the interactions with the nuclear pore complex to drive translocation of the INM protein to the nuclear side. In the nucleus, binding of RanGTP to β1 leads to the dissociation of the import complex. The INM protein may then be retained in the nucleus by interactions with chromatin in yeast (and/or the nuclear lamina in higher eukaryotes).

*This article and the paper concerned1 were published online on 23 August 2006.

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Wolf–Rayet star

Magnetar

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Mildly relativisticshockwave

of Mr 12,000, but lacking an NLS, showed that NLSs are not absolutely required for INM tar-geting5. Surprisingly, transport of this chimaera is energy dependent, but which step requires energy is unclear.

It may be that receptor-mediated transport is essential for two types of INM protein: those with domains of size, folding or charge that prevents passive diffusion; and those that are not retained stably in the nucleus. In higher eukaryotes, many INM proteins are retained by interaction with chromatin (DNA and associ-ated proteins) and/or with the nuclear lamina, a filamentous network that underlies the INM. As yeast cells have no nuclear lamina, it will be interesting to see whether nuclear retention of

yeast INM proteins is as important for INM targeting as it is in higher eukaryotes. ■

Ulrike Kutay and Petra Mühlhäusser are at the Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, 8093 Zurich, Switzerland.e-mails: ulrike.kutay@bc.biol.ethz.ch; petra.muehlhaeusser@bc.biol.ethz.ch

1. King, M. C., Lusk, C. P. & Blobel, G. Nature 442, 1003–1007 (2006).

2. Ellenberg, J. et al. J. Cell Biol. 138, 1193–1206 (1997).3. Smith, S. & Blobel, G. J. Cell Biol. 120, 631–637 (1993).4. Soullam, B. & Worman, H. J. J. Cell Biol. 120, 1093–1100

(1993).5. Ohba, T., Schirmer, E. C., Nishimoto, T. & Gerace, L. J. Cell

Biol. 167, 1051–1062 (2004).6. Saksena, S. et al. Nature Struct. Mol. Biol. 13, 500–508

(2006).

ASTROPHYSICS

Shock breakout caught on cameraTimothy R. Young

What exactly is the relationship between bursts of cosmic γ-rays and the stellar explosions known as supernovae? Intimate, it seems: highly magnetic neutron stars might even have spawned both.

Four papers in this issue1–4 present the first sightings of a remarkable cosmic event: the evolution of a hugely energetic γ-ray burst into a fully fledged stellar explosion — a super-nova. It’s the first time these two phenomena have been observed with the same telescope, NASA’s satellite-based Swift telescope, and the implication of a common origin for both is intriguing.

Supernovae most commonly occur when a mature star ceases to generate enough energy from thermonuclear fusion to support its own gravity. A catastrophic, explosive collapse ensues, during which material from over-lying stellar layers falls inwards. This creates a shockwave that rebounds outwards, fuelled by energy gained probably from internal magnetic fields and rotation. At ‘shock breakout’, when the shockwave emerges from the surface of the collapsing star, its energy is unleashed. It is sent out into space as radiation of all frequencies over a period of days to months — the classic signal of a supernova.

The idea that the comparatively short, sharp blast of a γ-ray burst (GRB) is perhaps some form of supernova early-warning signal had been around for some time, and over the past seven years, three candidate GRB–supernova pairings have been identified5–8. But no one had ever obtained the clinching evidence of a connection: witnessing the evolution of a γ-ray burst to the all-frequency display of a super-nova. In fact, no supernova had ever been observed at the moment of shock breakout.

That changes now, with observations at several wavelengths1–4 of an object — vari-ously known as supernova SN 2006aj and γ-ray burst GRB060218 — that flared up on

18 February 2006. All four papers make clear that the exploding object sent out both a slightly aspherical shockwave, typical of a supernova, and a jet-like stream of material characteristic of a GRB.

Using, respectively, X-ray data and opti-cal light curves, Campana et al. (page 1008)1 and Pian et al. (page 1011)2 show that the star concerned is a ‘Wolf–Rayet’ star that exploded while in a compact state, in which it contained no hydrogen or helium. That identification is supported by computer modelling presented by

Mazzali et al. (page 1018)3. Estimates, based on the X-ray data, of how a shell of gas at 2 million degrees expands constrained the radius of the progenitor to 1.2 × 107 km, much smaller than typical exploding stars1. The optical light curve and spectra are characteristic of the explosion of a bare carbon–oxygen stellar core2.

According to Campana et al.1, the X-ray spectra of the event exhibit two distinct components: a slightly off-spherical thermal component that is most probably explained by the heating effect of the supernova shockwave as it exited the star; and a highly directed non-thermal X-ray jet. The authors think that this jet can be ascribed to the classic GRB mecha-nism — radiation given off by highly relativistic gas, which travels at speeds only a thousandth of a percent lower than that of light. That emis-sion occurs most probably along the axis of rotation of an exploding star.

Pian et al.2 and Soderberg et al. (page 1014)4, on the other hand, observe that the peak flux of GRB060218 occurred at an energy of 5 kilo-electronvolts (keV), at the lower-energy end of the X-ray spectrum. Classic energetic GRBs have a peak in their emissions at an energy of around 250 keV. Thus, the observed event would be classified as a lower-energy ‘X-ray flash’, and might be incompatible with the clas-sic GRB model.

Interestingly, Soderberg et al.4 also find in their radio-frequency data the signature not of a highly relativistic jet, but of mildly relativis-tic expanding debris, travelling at just 90% the speed of light. This, again, is presumably a sig-nature of the supernova shockwave. Although the jet energy from the X-ray data1 indicated that GRB060218 was fainter overall than normal, the energy in the shockwave4 seems to imply that the supernova was brighter than usual. If the event had been further away from us — it is in fact the

Figure 1 | Shocking past. Data from NASA’s Swift telescope, together with ground-based follow-up observations of an object known as SN 2006aj/GRB060218 seem to indicate1–4 that γ-ray bursts (GRBs) and supernovae have a common origin in a collapsing Wolf–Rayet star. This object could have a highly magnetized compact object known as a magnetar at its core, which supplies the magnetic energy to produce both a highly relativistic jet (the GRB) and a mildly relativistic expanding shockwave. This shockwave produces radiation at all frequencies, the typical signature of a supernova explosion, when it breaks through the surface of the collapsing star slightly after the faster-moving GRB.

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