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    ON THE COVER
    Immunofluorescent micrograph showing the small intestine of a neonatal Myosin Vb knockout mouse, which has abnormalities including fused villi and intracellular inclusions in enterocytes. The inclusions arise from apical bulk endocytosis and contain apical markers such as phosphorylated ezrin-radixin-moesin (purple), which is normally exclusively located on the apical brush border and the brush border enzyme dipeptidyl peptidase IV (white). The endosomal protein, endotubin (yellow), below the brush border is also observed in inclusions forming at the apical membrane and the internalized inclusions. Image © Engevik et al., 2019. See https://doi.org/10.1083/jcb.201902063.

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ISSN 0021-9525
EISSN 1540-8140
In this Issue

People Ideas

Maeshima investigates the higher order structures and dynamics of chromatin.

Spotlights

Chaturvedi and VijayRaghavan highlight new findings from Schaub et al. about the transcriptional regulation of muscle reprogramming during development.

Brown and Koslover highlight recent work from Maza and colleagues that examines the mechanisms underlying compartmentalization of membrane proteins.

Napoli and Flores preview work from the Jackson laboratory showing that chemotherapy triggers macrophage-like features in tumor cells, which phagocyte other cells to outlast dormancy.

Reports

Super-resolution imaging combined with quantitative image analyses reveals dynamic spatial pattern formation of centriolar Plk4, a master regulator of centriole duplication. The self-organization properties of Plk4 exclusively provide the single site for centriole formation around the preexisting centriole.

Palani et al. reveal a new mechanism by which the F-actin binding protein tropomyosin is regulated. They find that phosphorylation of tropomyosin reduces its affinity for F-actin, allowing the competing Adf1 to bind and sever actin filaments.

Paternal mitochondria are removed during eukaryotic sexual reproduction to ensure maternal mitochondrial inheritance. Chacko et al. show that fission yeast uses an anchor protein to physically separate and tether parental mitochondria to the cortex during meiosis, thereby achieving uniparental mitochondrial inheritance.

The formation and differentiation of syncytial muscles is typically considered an irreversible developmental process. Schaub et al. describe molecular events that dedifferentiate syncytial muscle into mononucleate myoblasts during a naturally occurring lineage reprogramming process.

Articles

Kinetochores monitor their attachment to spindle microtubules to control spindle assembly checkpoint (SAC) signaling and cell cycle progression. Kuhn and Dumont show that individual mammalian kinetochores monitor the number of attached microtubules as a single unit in a sensitive and switch-like manner.

Hiraoka et al. identify SGK as the trigger kinase that initiates activation of cyclin B–Cdk1 at the meiotic G2/M transition in starfish oocytes. SGK is activated downstream of Gβγ by collaboration of PI3K-dependent and -independent pathways. These findings implicate SGK in M-phase entry.

Hosoda et al. show that SGK is required for an increase in intracellular pH (pHi) and cyclin B–Cdk1 activation upon meiotic resumption in starfish oocytes. The pHi increase is a prerequisite for chromosome transport and spindle assembly in ovarian oocytes.

This study reveals the role of Lissencephaly-1 (LIS1) in cargo-adapter–mediated dynein activation. Furthermore, it discovers a role of LIS1 in switching dynein from an autoinhibited conformation to an open conformation that can be activated by dynactin and cargo adapter.

Engevik et al. show that loss of myosin Vb results in the formation of large subapical vesicles, termed inclusions, lined by microvilli in small-intestinal enterocytes. Inclusions arise through apical bulk endocytosis of the brush border through a dynamin- and pacsin 2–dependent mechanism.

Su et al. show that seipin negatively regulates the production of sphingoid intermediates by binding the enzymes serine palmitoyltransferase and fatty acid elongase at discrete regions of the ER in close vicinity to lipid droplets, thereby mediating the synthesis of two major building blocks for sphingolipids.

Ishida and Bonifacino show that the small GTPase ARFRP1 functions upstream of two other small GTPases, ARL1 and ARL5, to coordinate the recruitment of two distinct classes of tethering factors, golgins and GARP, respectively, to the trans-Golgi network.

Kumar et al. describe a detailed pathway for channeling fat from the liver into blood across fed/fasted cycles. Insulin, phosphatidic acid, and kinesin collaborate in hepatocytes to deliver lipid droplets to the smooth ER, where they are catabolized to supply fat for lipoprotein production and secretion.

Nguyen et al. find that the PI(4)P phosphatase Sac2 localizes to insulin granules, where it controls granule docking to the plasma membrane. Loss of Sac2 results in impaired insulin secretion, and Sac2 mRNA levels are reduced in type 2 diabetes.

How cells sense direction in shallow and complex chemical gradients is not well understood. Wang et al. propose a deterministic model of yeast gradient sensing in which signaling, polarity, and trafficking proteins localize to the predetermined division site before redistributing upgradient by a directed treadmill-like mechanism.

Compartmentalization of peripheral membrane proteins is critical for normal neuron function and health, yet the mechanisms of compartmentalization remain poorly understood. Maza et al. have identified the intrinsic code for peripheral membrane protein enrichment within functional compartments of rod photoreceptors using powerful live cell imaging, biophysical, and computational approaches.

Mechanical cues from extracellular matrix exert strong effects on stem cell differentiation. This study finds that a signaling axis consisting of PINCH-1, Smurf1, and BMPR2 senses mechanical signals from extracellular matrix and regulates BMP signaling and mesenchymal stem cell differentiation.

Gerson-Gurwitz et al. show that FAMK-1, the sole Fam20-like secreted protein kinase in C. elegans, contributes to embryonic development and fertility, acts in the late secretory pathway, phosphorylates lectins, and is important in embryonic and tissue contexts where cells are subjected to mechanical strain.

Zaoui et al. provide the first mechanistic evidence supporting a regulatory mechanism for RhoB localization and stability by Arf6. These findings establish that Arf6 is essential for RhoB-specific subcellular targeting to endosomes and, thus, the regulation of membrane trafficking and cell motility following activation of the oncogenic receptor tyrosine kinase, Met.

The persistence of chemotherapy-induced senescent cancer cells is a barrier to achieving complete response. Tonnessen-Murray et al. reveal that these senescent cells acquire a phagocytic gene expression program and completely engulf and degrade whole cells in the lysosome, enhancing their survival.

Miao et al. show that a membrane trafficking pathway centered on Sbf and Rab35 is essential for the irreversibility of pulsed contractile events during apical constriction. Sbf/Rab35 disruption leads to a convoluted cell surface, suggesting that membrane remodeling is essential for the construction of effective actomyosin networks.

Tools

In this study, Bassaganyas et al. develop a powerful pooled genome-wide CRISPRi screen and uncover new factors for protein transport and secretion. This work opens new and stimulating perspectives for a deeper understanding of secretory pathway processes in health and disease.

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