bims-lypmec 2026-06-28 papers

EMBO J. 2026 Jun 22.

mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.

Nora S Siefert, Andrea Zanotti, Anastasija Paneva, Martin Schneider, Dominic Helm, Wilhelm Palm.

Acidification of lysosomes, endosomes and the Golgi underpins organelle-specific functions within the endomembrane system. This process is driven by vacuolar-type H + -ATPases (V-ATPases), proton pumps that reversibly assemble from peripheral V1 and membrane-integral Vo domains to regulate organelle pH. In yeast, V1-Vo assembly at the vacuole is mediated by the RAVE complex, but V-ATPase assembly in mammalian cells remains less well understood. Here, we systematically characterize physiological roles of the mammalian RAVE complex, composed of the subunits Dmxl1 or Dmxl2, Wdr7 and Rogdi. Under basal conditions, mRAVE broadly promotes V-ATPase assembly and luminal acidification of endomembrane organelles. Upon mTORC1 inactivation, mRAVE is recruited to lysosomes and required for the resulting increase in V-ATPase assembly and catabolic activity. Loss of mRAVE disrupts organelle acidification, leading to suppression of lysosomal catabolism, accumulation of dysfunctional lysosomes and lysosomal exocytosis. Restoring lysosomal pH rescues basal function in mRAVE-deficient cells but not the mTORC1-regulated increase in catabolic activity. Thus, mRAVE is an essential V-ATPase assembly factor that couples acidification to organelle function and nutrient signaling.

DOI: https://doi.org/10.1038/s44318-026-00838-5

J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):

PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.

Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.

Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.

DOI: https://doi.org/10.1083/jcb.202507087

Genes (Basel). 2026 May 31. pii: 643. [Epub ahead of print]17(6):

Next-Generation Sequencing and Variant Cataloguing for Screening and Diagnosis of Mucolipidoses and Other Lysosome-Related Organelle Disorders, Including Lysosomal Membrane or Transport Disorders.

Irina Vlasova-St Louis, Svetlana Khaiboullina.

Next-generation sequencing (NGS) has transformed the diagnostic landscape for inherited metabolic diseases by enabling high-resolution detection of pathogenic variants across genetically heterogeneous lysosomal pathways. This is particularly impactful for lysosomal diseases (LDs), including the mucolipidoses (ML I-IV), and for disorders involving lysosomal membranes, transporters, and lysosome-related organelles (LROs). These conditions often present with overlapping biochemical and clinical features that historically complicated accurate diagnosis. This review synthesizes current knowledge on the application of next-generation sequencing (NGS) technologies in the detection and interpretation of variants underlying mucolipidoses types I-IV and selected LRO and lysosomal membrane transport disorders. We summarize expanded variant catalogues, genotype-phenotype correlations, and functional evidence informing pathogenicity classification. In addition, we discuss the integration of NGS into newborn screening and population-level genomics. Collectively, these advances have refined disease definitions, resolved diagnostically challenging cases, and reshaped clinical workflows across the LD and LRO disease spectra.

Keywords: HPS; Hermansky-Pudlak syndrome type I–XI; lysosomal diseases; lysosome-related organelles; mucolipidoses types I–IV; next-generation sequencing; whole-exome sequencing; whole-genome sequencing

DOI: https://doi.org/10.3390/genes17060643

Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00655-8. [Epub ahead of print]45(7): 117577

Stiffness-induced impairment of GLUT4 trafficking in adult cardiomyocytes.

Alexia Vite, Tony Guo, Nesrine Bouhrira, Deborah M Eaton, Kenneth C Bedi, Claire F Brady, Jonathan J Edwards, Bea Duric, Keita Uchida, Cassidy Olsen, Lola Dong, Benjamin L Prosser, Zoltan Arany, Kenneth B Margulies.

Abnormal myocardial fuel utilization contributes to heart failure (HF). Myocardial glucose uptake in response to insulin is suppressed in patients with HF, but the mechanisms of this metabolic inflexibility are not fully understood. The present studies employ culture surfaces with tunable stiffness, quantitatively mimicking the healthy and diseased heart milieu. We observe that human and rat adult cardiomyocytes cultured on stiff surfaces develop blunted insulin-mediated glucose uptake, associated with intracellular aggregation of the high-affinity glucose transporter GLUT4 within the microtubule network, and with impaired contractility. These effects are prevented by blocking stiffness-induced detyrosination of α-tubulin, and can be partially rescued by metformin, through AMPK activation. Similarly, disabling motor proteins that mediate microtubule-based trafficking of GLUT4 independently alter insulin-mediated glucose uptake and contractility in myocytes. These findings demonstrate a cell-autonomous mechanism of stiffness-induced impairment of GLUT4 trafficking and glucose uptake in adult rat and human cardiomyocytes.

Keywords: AMPK; CP: cell biology; CP: metabolism; GLUT4; cardiac metabolism; cardiomyocytes; glucose uptakem; heart failure; insulin resistance; mechanical stress; microtubules; α-Tubulin detyrosination

DOI: https://doi.org/10.1016/j.celrep.2026.117577