bims-nocaut 2025-09-14 papers

Issue of 2025–09–14
three papers selected by
Quentin Frenger, University of Strasbourg

J Cell Biol. 2025 Oct 06. pii: e202503166. [Epub ahead of print]224(10):

ATG16L1 controls mammalian vacuolar proton ATPase.

Thabata L A Duque, Masroor Paddar, Einar Trosdal, Ruheena Javed, Lee Allers, Michal H Mudd, Prithvi Akepati, Soumya R Mishra, Michelle Salemi, Brett Phinney, Shawn B Bratton, Thomas Wileman, Vojo Deretic.

The mechanisms governing mammalian proton pump V-ATPase function are of fundamental and medical interest. The assembly and disassembly of cytoplasmic V1 domain with the membrane-embedded V0 domain of V-ATPase is a key aspect of V-ATPase localization and function. Here, we show that the mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. ATG16L1 knockout elevated V-ATPase activity, increased V1 presence on endomembranes, and increased the number of acidified intracellular compartments. ATG16L1's ability to efficiently bind V-ATPase was required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium tuberculosis infection in mice. These findings uncover a hitherto unappreciated role of ATG16L1 in regulating V-ATPase, a key pump governing acidification and functionality of the endolysosomal system along with its physiological roles.

DOI: https://doi.org/10.1083/jcb.202503166

EMBO J. 2025 Sep 11.

BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.

Michael G Hanna, Hely O Rodriguez Cruz, Kenshiro Fujise, Yumei Wu, C Shan Xu, Song Pang, Zhuonging Li, Mara Monetti, Pietro De Camilli.

Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show that one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region, and anchors them to lysosomes via its chorein domain-containing N-terminal region binding to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway, leading to lipidation and lysosomal recruitment of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with mATG8 which coincides with a dissociation from the vesicles. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage.

Keywords: BLTP3; LC3; Lysosome; Rab45; Urate Crystals

DOI: https://doi.org/10.1038/s44318-025-00543-9

Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01028-9. [Epub ahead of print]44(9): 116257

The E3 ubiquitin ligase SIAH1 targets a bacterial pore-forming toxin to facilitate xenophagy.

Min Wu, Xin Hu, Junpei Iibushi, Kazunori Murase, Takashi Nozawa, Ichiro Nakagawa.

Xenophagy, one form of selective autophagy, recognizes and eliminates the invading pathogen through the ubiquitination of bacterial surface components. Xenophagy is initiated by the damage of bacteria-surrounding endosomes by bacterial toxins; however, whether the host targets these xenophagy-inducible secretory factors to recognize bacteria remains unclear. Here, we report that E3 ligase SIAH1 recognizes and ubiquitinates streptolysin O (SLO), a pore-forming toxin secreted by group A Streptococcus (GAS). SIAH1 specifically recognizes the PSVP motif in SLO and mediates K48-linked polyubiquitination at Lys464. SIAH1 depletion significantly reduced GAS ubiquitination, impaired autophagosome formation, and enhanced bacterial survival. Studies with ATG16L1 and FIP200 knockout cell lines suggested that anti-GAS defense involves sequential deployment of the LC3-associated phagocytosis-like (LAP-like) process followed by canonical autophagy, and SIAH1 coordinates these pathways. Our findings reveal SIAH1's crucial role in bacterial toxin recognition and demonstrate a mechanism in which bacterial virulence factors themselves become targets of host xenophagy machinery.

Keywords: CP: Microbiology; E3 ligase; LC3-associated phagocytosis; SIAH 1; group A Streptococcus; streptolysin O; ubiquitin; xenophagy

DOI: https://doi.org/10.1016/j.celrep.2025.116257