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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Tools

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.

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.

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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.

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