ON THE COVER
Collage of HeLa cells stained with a phospho-specific antibody to the kinetochore protein Hec1 (pS69, shown in green). S69 remains highly phosphorylated throughout all stages of mitosis. Chromosomes are pseudo-colored according to mitotic phase (purple, prophase; blue, early prometaphase; light blue, midprometaphase; magenta, metaphase; and yellow, anaphase). Microtubules are shown in red. Images were acquired using an Olympus 60X Plan Apo objective on a DeltaVision personalDV system. Image © DeLuca et al., 2018.
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People & Ideas
Woodruff previews work from Huang et al. proposing how phase separtaion of a scaffold protein could facilitate spindle assembly.
ER–mitochondria contacts: Actin dynamics at the ER control mitochondrial fission via calcium release
Steffen and Koehler preview work from the Chakrabarti et al. presenting new ways in which actin polymerization at the endoplasmic reticulum influences mitochondrial division.
Protein sequestration at the nuclear periphery as a potential regulatory mechanism in premature aging
Serebryannyy and Misteli provide a perspective on how protein sequestration at the inner nuclear membrane and nuclear lamina might influence aging.
Hu et al. discuss challenges in studying aging and offer a perspective on the use of organoids as a model to understand the biology of aging.
Klaips et al. outline the pathways and molecular mechanisms of cellular protein homeostasis, or proteostasis, and discuss how a decline in proteostasis during aging contributes to disease.
McHugh and Gil review the role of senescence in age-related diseases and how targeting senescence may improve health span and extend life span.
Keyes and Fuchs discuss the decline in stem cell renewal and function with aging and the ensuing consequences on tissue homeostasis and regeneration.
Templeman and Murphy review how key nutrient-sensing signaling pathways—the insulin/IGF-1, mTOR, and AMPK pathways—regulate and coordinate reproductive and somatic aging.
Mitotic spindle component BuGZ is known to undergo phase separation. Huang et al. show that BuGZ promotes Aurora A phosphorylation and activation and that this is inhibited when BuGZ phase separation is disrupted.
Specialized ribosomes and specific ribosomal protein paralogs control translation of mitochondrial proteins
Ribosomal proteins exist mainly as paralog pairs in eukaryotes, yet the reasons for maintaining duplication are unclear. By using a novel proteomic approach, Segev and Gerst show paralog-specific regulation of the translation of mitochondrial proteins using specialized ribosomes.
Lipid droplets (LDs) are essential organelles for cellular energy homeostasis, but how metabolic cues are integrated in their life cycle is unclear. Teixeira et al. find that two protein isoforms, Ldo16 and Ldo45, differentially regulate LD dynamics under nutrient-rich and -deprived conditions, linking energy metabolism and storage.
The turnover of mitochondrial outer-membrane proteins is known to be mediated by the cytoplasmic ubiquitin–proteasome pathway. Wu et al. report the unexpected finding that two outer-membrane proteins Tom22 and Om45 are inwardly translocated into mitochondria and degraded by the inner-membrane protease Yme1.
PDGFRα signals from cilia to control development and tumorigenesis. Schmid et al. now show that intraflagellar transport protein 20 (IFT20) interacts with and stabilizes the E3 ubiquitin ligases c-Cbl and Cbl-b to promote feedback inhibition of PDGFRα signaling at the primary cilium.
Precise regulation of kinetochore–microtubule attachments is essential for successful chromosome segregation. DeLuca et al. show that Aurora A kinase regulates kinetochore–microtubule dynamics of metaphase chromosomes through phosphorylation of Hec1 S69, a previously uncharacterized phosphorylation target site on the Hec1 tail.
Cyclin B1 is essential for mitosis in mouse embryos, and its nuclear export sets the time for mitosis
Strauss and colleagues show that the Cyclin B1 protein is essential to make cells divide and that this protein must be constantly transported out of the nucleus to prevent cells dividing at the wrong time.
Centrosome clustering is essential for the survival of cells containing supernumerary centrosomes. Rhys et al. show that centrosome clustering is a two-step mechanism in which increased cortical contractility, driven by loss of E-cadherin, restricts centrosome movement, facilitating HSET-mediated clustering.
Local actin filament formation powers the development of the signal-receiving arbor of neurons. In this study, Izadi et al. demonstrate that Cobl-like, which bears only a single WH2 domain, mediates dendritic branching by coordinating with the F-actin–binding protein Abp1 in a Ca2+/CaM-controlled manner to control actin dynamics.
MRCKα is activated by caspase cleavage to assemble an apical actin ring for epithelial cell extrusion
Apoptotic cell extrusion is critical for the maintenance of epithelial functionality and relies on complex morphological events mediated by the actomyosin cytoskeleton. Gagliardi et al. show that caspase-mediated cleavage of MRCKα triggers the assembly of an apical actin ring and apoptotic epithelial extrusion.
INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division
Actin polymerization through the ER-bound formin INF2 stimulates mitochondrial division by promoting Drp1 recruitment. Chakrabarti et al. extend this work to show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: increased ER–mitochondrial calcium transfer via MCU and inner mitochondrial membrane constriction, which requires electron transport chain activity.
Eisenberg-Bord et al. describe a lipid droplet (LD) subpopulation with a unique proteome, which is adjacent to the nucleus–vacuole junction contact site. They identify the LD machinery, which cooperates with the lipodystrophy factor seipin as a key determinant of LD identity and suggest a mechanism for functional organelle diversification.
The TRAPP complexes are nucleotide exchange factors that activate Rab GTPases, and four different versions of TRAPP have been reported. Thomas et al. show that only two versions of TRAPP are detectable in normal cells and demonstrate that the TRAPPIII complex regulates Golgi trafficking in addition to its established role in autophagy.
RAB-10 is a master regulator of endocytic recycling in polarized epithelial cells. Liu et al. identify LET-413, the Caenorhabditis elegans homolog of Scrib/Erbin, as a RAB-5 effector that is required for the DENN-4–mediated activation of RAB-10 and the control of membrane expansion in the C. elegans intestine.
Autophagy can suppress inflammation, and it is unclear how immune cells escape this suppression when necessary. He et al. show that p38α MAPK activated by proinflammatory signals relieves autophagic control of inflammation by phosphorylating and inhibiting ULK1. This mechanism regulates microglial immune responses and may be involved in neuroinflammatory diseases.
Specific changes in phospholipid content are a hallmark of the membranes of maturing endosomes and phagosomes, but is it unclear how this is controlled. Naufer et al. now show that acidification of the lumen of endosomes and phagosomes triggers dissociation of the Vps34 lipid kinase from these organelles, which terminates PtdIns(3)P synthesis and signaling.
The class III phosphatidylinositol 3-kinase VPS-34 promotes phagosome closure and maturation. Liu et al. identify UBC-13 as an E2-conjugating enzyme working with the E3 ligase CHN-1 to catalyze K63-linked poly-ubiquitination on VPS-34, which promotes VPS-34 stability and phagosome maturation.
During crinophagy, secretory granules directly fuse with lysosomes to degrade their contents. Csizmadia et al. show that excess glue granules in Drosophila salivary glands are degraded by crinophagy at the onset of metamorphosis. Glue granule–lysosome fusion requires the HOPS tether, Rab2, Rab7, and a SNARE complex consisting of Syntaxin 13, Snap29, and Vamp7.
The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but how it potentiates tumor cell invasiveness is unclear. Genna et al. find that Pyk2 and the closely related kinase FAK modulate breast cancer cell invasiveness by distinct mechanisms and coordinate the balance between focal adhesion–mediated migration and invadopodia-dependent extracellular matrix invasion.
Li and Springer demonstrate differences between integrins α4β1 and α5β1 in intrinsic affinities and relative free energies of three conformational states. Integrin conformational equilibria are both subunit and cell type specific. The energy landscapes of intact receptors on the cell surface provide a framework for understanding regulation of integrin adhesiveness.
Primary cilia are essential for normal development and tissue homeostasis, but the mechanisms that remodel the centriole to promote cilia initiation are not well understood. Agbu et al. report that mouse RSG1, a small GTPase, regulates a late step in cilia initiation, downstream of TTBK2 and the CPLANE protein INTU.