Nature Cell Biology 10, 1257 (2008). doi:10.1038/ncb1784

Authors: Danelle Devenport & Elaine Fuchs

Nature Cell Biology 10, 1291 (2008). doi:10.1038/ncb1787

Authors: Klaus H. Hansen, Adrian P. Bracken, Diego Pasini, Nikolaj Dietrich, Simmi S. Gehani, Astrid Monrad, Juri Rappsilber, Mads Lerdrup & Kristian Helin

Nature Cell Biology 10, 1280 (2008). doi:10.1038/ncb1786

Authors: Ray Kit Ng, Wendy Dean, Claire Dawson, Diana Lucifero, Zofia Madeja, Wolf Reik & Myriam Hemberger

Nature Cell Biology 10, 1269 (2008). doi:10.1038/ncb1785

Authors: Shinsuke Niwa, Yosuke Tanaka & Nobutaka Hirokawa

Nature Cell Biology 10, 1324 (2008). doi:10.1038/ncb1791

Authors: Kyoko Arimoto, Hiroyuki Fukuda, Shinobu Imajoh-Ohmi, Haruo Saito & Mutsuhiro Takekawa

When confronted with environmental stress, cells either activate defence mechanisms to survive, or initiate apoptosis, depending on the type of stress. Certain types of stress, such as hypoxia, heatshock and arsenite (type 1 stress), induce cells to assemble cytoplasmic stress granules (SGs), a major adaptive defence mechanism. SGs are multimolecular aggregates of stalled translation pre-initiation complexes that prevent the accumulation of mis-folded proteins. Type 2 stress, which includes X-rays and genotoxic drugs, induce apoptosis through the stress-activated p38 and JNK MAPK (SAPK) pathways. A functional relationship between the SG and SAPK responses is unknown. Here, we report that SG formation negatively regulates the SAPK apoptotic response, and that the signalling scaffold protein RACK1 functions as a mediator between the two responses. RACK1 binds to the stress-responsive MTK1 MAPKKK and facilitates its activation by type 2 stress; however, under conditions of type 1 stress, RACK1 is sequestered into SGs. Thus, type 1 conditions suppress activation of the MTK1–SAPK pathway and apoptosis induced by type 2 stress. These findings may be relevant to the problem of hypoxia-induced resistance to cancer chemotherapy.

Nature Cell Biology 10, 1309 (2008). doi:10.1038/ncb1789

Authors: Mads Gyrd-Hansen, Maurice Darding, Maria Miasari, Massimo M. Santoro, Lars Zender, Wen Xue, Tencho Tenev, Paula C.A. da Fonseca, Marketa Zvelebil, Janusz M. Bujnicki, Scott Lowe, John Silke & Pascal Meier

The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-κB signalling and cell survival. The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation. Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2–MALT1 to activate NF-κB. Our data suggest that the UBA domain of cIAP2–MALT1 stimulates NF-κB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2–MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2–MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-κB signalling and oncogenesis.

Nature Cell Biology 10, 1333 (2008). doi:10.1038/ncb1792

Authors: Xijing Han, Xiaolan Feng, Jerome B. Rattner, Heather Smith, Pinaki Bose, Keiko Suzuki, Mohamed A. Soliman, Michelle S. Scott, Brian E. Burke & Karl Riabowol

ING proteins interact with core histones through their plant homeodomains (PHDs) and with histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to alter chromatin structure. Here we identify a lamin interaction domain (LID) found only in ING proteins, through which they bind to and colocalize with lamin A. Lamin knockout (LMNA−/−) cells show reduced levels of ING1 that mislocalize. Ectopic lamin A expression increases ING1 levels and re-targets it to the nucleus to act as an epigenetic regulator. ING1 lacking the LID does not interact with lamin A or affect apoptosis. In LMNA−/− cells, apoptosis is not affected by ING1. Mutation of lamin A results in several laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), a severe premature ageing disorder. HGPS cells have reduced ING1 levels that mislocalize. Expression of LID peptides to block lamin A–ING1 interaction induces phenotypes reminiscent of laminopathies including HGPS. These data show that targeting of ING1 to the nucleus by lamin A maintains ING1 levels and biological function. Known roles for ING proteins in regulating apoptosis and chromatin structure indicate that loss of lamin A–ING interaction may be an effector of lamin A loss, contributing to the HGPS phenotype.

Nature Cell Biology 10, 1356 (2008). doi:10.1038/ncb1795

Authors: Maiko Higuchi, Keisuke Onishi, Chikako Kikuchi & Yukiko Gotoh

Many extracellular signals stimulate phosphatidylinositol-3-kinase, which in turn activates the Rac1 GTPase, the protein kinase Akt and the Akt Thr 308 upstream kinase PDK1. Active Rac1 stimulates a number of events, including substrate phosphorylation by a subgroup of the PAK family of kinases. The combined effects of Rac1, PDK1 and Akt are crucial for cell migration, growth, survival, metabolism and tumorigenesis. Here we show that Rac1 stimulates a second, kinase-independent function of PAK1. The PAK1 kinase domain serves as a scaffold to facilitate Akt stimulation by PDK1 and to aid recruitment of Akt to the membrane. PAK differentially activates subpopulations of Akt. These findings reveal scaffolding functions of PAK that regulate the efficiency, localization and specificity of the PDK1–Akt pathway.

Nature Cell Biology 10, 1349 (2008). doi:10.1038/ncb1794

Authors: Sachie Hiratsuka, Akira Watanabe, Yoshiko Sakurai, Sachiko Akashi-Takamura, Sachie Ishibashi, Kensuke Miyake, Masabumi Shibuya, Shizuo Akira, Hiroyuki Aburatani & Yoshiro Maru

A large number of macrophages and haematopoietic progenitor cells accumulate in pre-metastatic lungs in which chemoattractants, such as S100A8 and S100A9, are produced by distant primary tumours serving as metastatic soil. The exact mechanism by which these chemoattractants elicit cell accumulation is not known. Here, we show that serum amyloid A (SAA) 3, which is induced in pre-metastatic lungs by S100A8 and S100A9, has a role in the accumulation of myeloid cells and acts as a positive-feedback regulator for chemoattractant secretion. We also show that in lung endothelial cells and macrophages, Toll-like receptor (TLR) 4 acts as a functional receptor for SAA3 in the pre-metastatic phase. In our study, SAA3 stimulated NF-κB signalling in a TLR4-dependent manner and facilitated metastasis. This inflammation-like state accelerated the migration of primary tumour cells to lung tissues, but this was suppressed by the inhibition of either TLR4 or SAA3. Thus, blocking SAA3–TLR4 function in the pre-metastatic phase could prove to be an effective strategy for the prevention of pulmonary metastasis.

Nature Cell Biology 10, 1301 (2008). doi:10.1038/ncb1788

Authors: Hongbin Li, Fengli Guo, Boris Rubinstein & Rong Li

Movement of meiosis I (MI) chromosomes from the oocyte centre to a subcortical location is the first step in the establishment of cortical polarity. This is required for two consecutive rounds of asymmetric meiotic cell divisions, which generate a mature egg and two polar bodies. Here we use live-cell imaging and genetic and pharmacological manipulations to determine the force-generating mechanism underlying this chromosome movement. Chromosomes were observed to move toward the cortex in a pulsatile manner along a meandering path. This movement is not propelled by myosin-II-driven cortical flow but is associated with a cloud of dynamic actin filaments trailing behind the chromosomes/spindle. Formation of these filaments depends on the actin nucleation activity of Fmn2, a formin-family protein that concentrates around chromosomes through its amino-terminal region. Symmetry breaking of the actin cloud relative to chromosomes, and net chromosome translocation toward the cortex require actin turnover.

Nature Cell Biology 10, 1341 (2008). doi:10.1038/ncb1793

Authors: Nana Naetar, Barbara Korbei, Serguei Kozlov, Marc A. Kerenyi, Daniela Dorner, Rosana Kral, Ivana Gotic, Peter Fuchs, Tatiana V. Cohen, Reginald Bittner, Colin L. Stewart & Roland Foisner

Lamina-associated polypeptide (LAP) 2α is a chromatin-associated protein that binds A-type lamins. Mutations in both LAP2α and A-type lamins are linked to human diseases called laminopathies, but the molecular mechanisms are poorly understood. The A-type lamin–LAP2α complex interacts with and regulates retinoblastoma protein (pRb), but the significance of this interaction in vivo is unknown. Here we address the function of the A-type lamin–LAP2α complex with the use of LAP2α-deficient mice. We show that LAP2α loss causes relocalization of nucleoplasmic A-type lamins to the nuclear envelope and impairs pRb function. This causes inefficient cell-cycle arrest in dense fibroblast cultures and hyperproliferation of epidermal and erythroid progenitor cells in vivo, leading to tissue hyperplasia. Our results support a disease-relevant model in which LAP2α defines A-type lamin localization in the nucleoplasm, which in turn affects pRb-mediated regulation of progenitor cell proliferation and differentiation in highly regenerative tissues.

Nature Cell Biology 10, 1365 (2008). doi:10.1038/ncb1796

Authors: Adeline Vitaliano-Prunier, Alexandra Menant, Maria Hobeika, Vincent Géli, Carole Gwizdek & Catherine Dargemont

Mono-ubiquitylation of histone H2B correlates with transcriptional activation and is required for di- and trimethylation at Lys 4 on the histone H3 tail (H3K4) by the SET1/COMPASS methyltransferase complex through a poorly characterized trans-tail pathway. Here we show that mono-ubiquitylation of histone H2B promotes ubiquitylation at Lys 68 and Lys 69 of Swd2, the essential component of SET1/COMPASS in Saccharomyces cerevisiae. We found that Rad6/Bre1 ubiquitylation enzymes responsible for H2B ubiquitylation also participate directly in Swd2 modification. Preventing Swd2 or H2B ubiquitylation did not affect Set1 stability, interaction of Swd2 with Set1 or the ability of Swd2 to interact with chromatin. However, we found that mutation of Lys 68 and Lys 69 of Swd2 markedly reduced trimethylation, and to a lesser extent dimethylation, of H3K4 at the 5′-end of transcribing genes without affecting monomethylation. This effect results from the ability of Swd2 ubiquitylation to control recruitment of Spp1, a COMPASS subunit necessary for trimethylation. Our results further indicate that Swd2 is a major H3-binding component of COMPASS. Swd2 thus represents a key factor that mediates crosstalk between H2B ubiquitylation and H3K4 trimethylation on chromatin.

Nature Cell Biology 10, 1318 (2008). doi:10.1038/ncb1790

Authors: Hongyan Xing, Nathan L. Vanderford & Kevin D. Sarge

To maintain phenotypes of cell lineages, cells must 'remember' which genes were active before mitosis entry and transmit this information to their daughter cells so that expression patterns can be faithfully re-established in G1. This phenomenon is called gene bookmarking. However, during mitosis transcription ceases, most sequence-specific proteins dissociate from DNA and the chromatin is tightly compacted, making it difficult to understand how gene activity 'memory' is maintained through this stage of the cell cycle. A feature of gene bookmarking is that in mitotic cells, the promoters of formerly active genes lack compaction, but how compaction of these regions is inhibited is unknown. Here we show that during mitosis, TATA-binding protein (TBP), which remains bound to DNA during mitosis, recruits PP2A. TBP also interacts with condensin to allow efficient dephosphorylation and inactivation of condensin near these promoters to inhibit their compaction. Further, ChIP-on-chip data show that TBP is bound to many chromosomal sites during mitosis, and is higher in transcribed regions but low in regions containing pseudogenes and genes whose expression is tissue-restricted. These results suggest that TBP is involved not only in gene transcription during interphase but also in preserving the memory of gene activity through mitosis to daughter cells.

Nature Cell Biology 10, 1251 (2008). doi:10.1038/ncb1108-1251

Author: Jeffrey D. Axelrod

Mammalian hairs have characteristic patterns of orientation, with a predominantly rostral to caudal direction, occasional swirls and a high level of local correlation between hairs. A detailed new study demonstrates that the polarity of hairs derives from an underlying planar polarity of the basal epidermal cells from which hair follicles arise.

Nature Cell Biology 10, 1253 (2008). doi:10.1038/ncb1108-1253

Author: Andrea H. Brand

The balance between proliferation and differentiation is essential not only for the generation and maintenance of tissues, but also to prevent uncontrolled cell division and tumorigenesis. The mitotic kinase Aurora A coordinates cell-cycle events and asymmetric division by regulating localization of the cell fate determinant Numb through remodelling of the conserved PAR polarity complex.

Nature Cell Biology 10, 1249 (2008). doi:10.1038/ncb1108-1249

Author: Jane Mellor

Trans-tail regulation is the linked post-translational modification of tails on different histones. Two important studies implicate Swd2 as the link between H2B ubiquitylation and H3 methylation. Swd2 is a component of both the SET1 methyltransferase complex and the cleavage and polyadenylation factor CPF, implicating trans-tail regulation in differentiating events at the beginning and end of genes.

Nature Cell Biology 10, 1233 (2008). doi:10.1038/ncb1108-1233

This year's Nobel Prizes mark the most significant technological advance in cell biology, GFP et al., as well as two discoveries in virology with major health implications.