ON THE COVER
Confocal image of a RAW264.7 macrophage expressing the GFP-tagged Lamellipodin mutant that does not bind Ena/Vasp (LpdEVmut) showing formation of phagocytic cups during IgG-mediated phagocytosis. Image © Montaño-Rendón et al., 2022 https://doi.org/10.1083/jcb.202207042
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People & Ideas
Elvan Böke: Long live the oocyte
Elvan Böke investigates the mechanisms that preserve the viability of dormant oocytes.
Lipid droplets go through a (liquid crystalline) phase
Windham and Cohen preview work from Rogers et al. showing that triglyceride lipolysis promotes liquid crystalline phase transitions in lipid droplets (LDs) as well as changes in the LD proteome.
SPIN(DLY)-OFF: A tale of conformational change to control DYNEIN
Barbosa et al. discuss work by Mussachio and colleagues finding that conformational changes in the DYNEIN adaptor SPINDLY can precisely control DYNEIN activation at kinetochores.
A second chance at yeast early endosomes
Proteins internalized from the cell surface can be degraded or return to the surface through protein recycling. Laidlaw and colleagues define a protein recycling pathway that operates from an early endosome in yeast.
Cholesterol: Enhancing FGF2 translocation in unconventional secretion
Wang et al. discuss work from the Nickel laboratory on unconventional protein secretion, showing that cholesterol promotes the secretion of fibroblast growth factor 2 (FGF2) by enhancing PI(4,5)P2 accessibility and altering membrane properties to increase FGF2 translocation.
Lysosomal solute and water transport
Hu et al. review the regulation of lysosome size by ion and water transport across lysosomal membranes.
NBR1: The archetypal selective autophagy receptor
Rasmussen et al. discuss NBR1 as the archetypical selective autophagy receptor, as well as its known cargos, roles in diseases, and collaboration with p62.
Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
Using a viral-induced hypomorph of GBF1, Navare et al. demonstrate that the principle of synthetic lethality is a mechanism to selectively kill virus-infected cells.
Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation
Chakrabarti, Fung et al. show that Arp2/3 complex-dependent actin polymerization is necessary for the rapid glycolytic increase that accompanies treatments that compromise mitochondrial function, including mitochondrial depolarization, electron transport chain-inhibiting drugs, hypoxia, and mutation of mitochondrial proteins. The relevant actin population is likely to polymerize around the mitochondria themselves.
Triglyceride lipolysis triggers liquid crystalline phases in lipid droplets and alters the LD proteome
Lipid droplets (LDs) can exhibit liquid crystalline sterol-esters in vivo, but the mechanisms governing this are unclear. Rogers et al. describe how yeast glucose restriction drives triglyceride lipolysis that promotes liquid crystalline phase transitions within LDs. They also investigate how these phase transitions alter the LD proteome.
Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage
Lysosomal damage induces stress granule (SG) formation and translational reprograming. The newly appreciated process of atg8ylation affects SG formation and concomitantly recruits SG core proteins NUFIP2 and G3BP1 to damaged lysosomes. These proteins independently of SG condensates and in coordination with galectin-8 inactivate mTOR via the Ragulator–Rag complex.
Non-catalytic allostery in α-TAT1 by a phospho-switch drives dynamic microtubule acetylation
α-TAT1 acetylates microtubules; however, regulatory mechanisms of the enzyme remain unknown. We report that its disordered region consisting of three functional elements—nuclear export, phospho-inhibited nuclear import, and 14-3-3–mediated cytoplasmic retention—intricately determines both α-TAT1 subcellular localization and levels of microtubule acetylation.
The lectin Discoidin I acts in the cytoplasm to help assemble the contractile machinery
Ly T.S. Nguyen and Douglas N. Robinson found that the lectin Discoidin I plays roles intracellularly within the contractile machinery. Specifically, Discoidin functions as a component of the mechanoresponsive contractility kits and regulates the localization and activity of Cortexillin I, an important mechanoresponsive protein of this system.
Conformational transitions of the Spindly adaptor underlie its interaction with Dynein and Dynactin
d’Amico et al. report a structure-function analysis of Spindly, a Dynein–Dynactin adaptor that functions at kinetochores during mitosis. They propose that Spindly is auto-inhibited. Its binding to two distinct kinetochore triggers, the RZZ complex and an unknown receptor, promotes conformational changes that unleash the Dynein–Dynactin adaptor activity of Spindly.
Type II phosphatidylinositol 4-kinases function sequentially in cargo delivery from early endosomes to melanosomes
Contents are delivered to maturing melanosomes from early endosomal intermediates through tubular transport carriers. Zhu et al. show that two type II phosphatidylinositol kinases, PI4KIIα and PI4KIIβ, sequentially generate phosphatidylinositol-4-phosphate during tubule initiation and elongation for ultimate melanosome content delivery.
PI4P and BLOC-1 remodel endosomal membranes into tubules
Tubular recycling endosomes originate from early endosomes to deliver contents to target membranes. Jani et al. show that BLOC-1 and PI4P (synthesized by PI4KIIs) remodel membranes to generate and stabilize recycling tubules for cargo trafficking and exploitation by pathogens.
The low-density lipoprotein receptor–mTORC1 axis coordinates CD8+ T cell activation
Increased cholesterol uptake by the LDLR contributes to the immunometabolic response of activated CD8+ T cells through the modulation of lysosome–mTORC1 axis. This finding paves the way for cell-selective targeting of the LDLR to boost CD8-dependent immune response.
Recycling of cell surface membrane proteins from yeast endosomes is regulated by ubiquitinated Ist1
Laidlaw et al. show nutrient transporters rapidly internalize to an early endosome population. Substrate withdrawal triggers endosomal recycling of transporters from endosomes back to the surface in a pathway that relies on ubiquitination of the ESCRT protein Ist1 and the associated factors Cdc48 and Npl4.
Cholesterol promotes clustering of PI(4,5)P2 driving unconventional secretion of FGF2
This work demonstrates the lipid composition and the corresponding biophysical properties of biological membranes to tune highly specific protein–lipid interactions. Specifically, cholesterol is shown to affect phosphoinositide-dependent membrane recruitment and translocation into the extracellular space of FGF2, a survival factor involved in tumor-induced angiogenesis.
Spatiotemporal control of actomyosin contractility by MRCKβ signaling drives phagocytosis
Phagocytosis by different cell types is essential for tissue homeostasis and function. This study identifies a Cdc42-based dual effector signaling mechanism that drives actomyosin remodeling and, thereby, internalization of phagocytic ligands in retinal pigment epithelial cells.
PtdIns(3,4)P2, Lamellipodin, and VASP coordinate actin dynamics during phagocytosis in macrophages
Class I PI 3-kinase is required for phagocytosis. This study investigates the role of PI3,4P2 produced downstream of PI 3-Kinase in phagocytosis. PI3,4P2, its effector-binding protein Lamellipodin, and VASP are required to support actin-driven pseudopod extension and engulfment of IgG opsonized particles.
In vivo 3D profiling of site-specific human cancer cell morphotypes in zebrafish
Determining the influences of tissue microenvironment on cancer cell states in vivo remains a challenge. Segal et al. present a quantitative high-resolution imaging assay of single cancer cell morphology in zebrafish xenografts to probe functional adaptation to variable cell-extrinsic cues and molecular interventions.
Quality assessment in light microscopy for routine use through simple tools and robust metrics
Faklaris et al. present tools, fast and robust acquisition protocols, and automated analysis methods to assess quality control metrics for light fluorescence microscopy. The authors collected data from 10 light microscopy core facilities and propose guidelines to ensure quantifiable and reproducible results among laboratories.