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The activity state of integrins is crucial for cell adhesion, migration and differentiation, and is regulated predominantly by protein interactions of the integrin β cytoplasmic domain. SHARPIN is now shown to negatively regulate integrin activation by binding the α-integrin subunit and interfering with the association of the β cytodomain with activating proteins.
In the competitive world of scientific publishing, it is essential to communicate research findings in a clear and accessible manner. Scientists should develop the ability to write well-structured and compelling cover letters, manuscripts and rebuttal letters.
Caspase 8 is known to suppress necroptosis, but its relevant target protein was unknown. Ting and colleagues show that caspase 8 cleaves the deubiquitylase CYLD to inhibit necroptosis and promote cell survival.
Somatic reprogramming efficiency by expression of defined transcription factors can be enhanced by deletion of p53. He and colleagues found that the microRNA miR-34, which is induced by p53 during reprogramming, inhibits reprogramming, partly by direct repression of pluripotency factors. Deletion of Mir34 from mice increases reprogramming efficiency and kinetics without affecting self-renewal and differentiation.
The MYC proto-oncogene modulates transcription through binding to E-boxes. Di Croce and colleagues find that PAK-2-mediated phosphorylation confers a tumour-suppressive function to MYC, in which MYC cooperates with differentiation signals to positively modulate the transcription of genes targeted by retinoic acid, independently of E-boxes.
Aragón and colleagues show that the phosphatase Cdc14 acts on the CDT subunit of RNA polymerase II to silence transcription of repetitive regions of the yeast genome. At telomeres this event promotes condensin loading and mitotic segregation.
The p97 AAA+ ATPase (also known as VCP) functions in various ubiquitin-regulated processes. Ramadan and colleagues now find that p97 is recruited to sites of DNA damage by Lys-48-linked ubiquitin chains, which are formed in a process mediated by RNF8. p97 then removes Lys-48–ubiquitin conjugates and promotes recruitment of DNA-repair factors.
An epithelial cell can be engulfed by its neighbour through entosis, which frequently results in the death of the entosed cell. Overholtzer and colleagues show that the autophagy machinery is recruited to single-membrane entotic vacuoles and promotes their fusion with lysosomes. Single-membrane macrophage phagosomes containing apoptotic cells are also targeted for destruction by the autophagy pathway.
Misfolded proteins are potentially toxic and are therefore subjected to highly selective degradation by the ubiquitin–proteasome system. The identification of the Hul5 ubiquitin ligase as a major mediator of such 'quality-control' ubiquitylation following heat shock raises new questions about the design of these pathways.
In mammalian cells, long-range vesicular transport is thought to occur via microtubule tracks. However, Schuh reports the existence of an actin-based pathway for long-range trafficking in mouse oocytes by showing that Rab11a-positive vesicles are decorated with actin-nucleating formin proteins. She finds that these proteins assemble actin networks that guide vesicles to the cell surface.
PAR polarity proteins are asymmetrically localized at the cortex of Caenorhabditis elegans zygotes. Seydoux and colleagues show that aPKC-mediated phosphorylation of PAR-2, which inhibits recruitment of PAR-2 to the cortex, is directly inhibited by microtubules emanating from the sperm-donated centrosomes. This protection allows PAR-2, and subsequently the PAR-1 kinase to access the cortex nearby the sperm, thus defining the posterior of the embryo. PAR-1 in turn phosphorylates PAR-3 to induce dissociation of PAR-3–aPKC from the posterior.
Spector and colleagues demonstrate that transcriptional activation after mitosis occurs with much faster kinetics than in interphase. Increased acetylation of lysine 5 on histone H4 is maintained during mitosis to recruit bromodomain protein 4, which then facilitates chromatin decompaction for transcriptional reactivation.
The ubiquitin–proteasome system clears misfolded proteins to maintain cellular homeostasis. Mayor and colleagues identify the ubiquitin ligase Hul5 as a critical component of the heat-shock response and show that it selectively targets misfolded cytosolic proteins for degradation.