bims-nocaut 2026-03-22 papers

Issue of 2026–03–22
three papers selected by
Quentin Frenger, University of Strasbourg

EMBO J. 2026 Mar 20.

Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.

Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.

Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.

Keywords: Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation

DOI: https://doi.org/10.1038/s44318-026-00741-z

Autophagy. 2026 Mar 20. 1-9

ATG8 and protein ATG8ylation - more than just Another TaG?

Fabian Gerth, Simone Kosol, Natasha Aley, Alexander Agrotis, Robin Ketteler.

Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for autophagosome number, size and composition. A lot of research has focussed on its function in forming complexes required for autophagosome-lysosome fusion or generally, its interaction with other proteins via the ATG8-family interacting motif/AIM. Many additional functions have been discovered, for instance in non-canonical autophagy processes and in the nucleus. The list of known functions of ATG8 are ever expanding, and, most recently, evidence has emerged that, similar to ubiquitin, ATG8 can modify proteins by covalent attachment to a lysine residue (protein ATG8ylation). In this review, we aim to summarize the current literature on protein ATG8ylation and highlight the currently known substrates. We propose strategies to investigate this modification and provide an outlook for its possible cellular function.Abbreviations: ATG: autophagy related; DUBs: de-ubiquitinating enzymes; GABARAPL: GABA type A receptor associated protein like; GIR: GABARAP-interacting region; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; RMSD: root mean square; UBL: ubiquitin-like; UPS: ubiquitin-proteasome-system.

Keywords: ATG4B; ATG8; ATG8ylation; LC3ylation; autophagy; ubiquitin-like

DOI: https://doi.org/10.1080/15548627.2026.2642981

Autophagy. 2026 Mar 18. 1-2

ATG2A connects lipid droplets and the ER to regulate lipid storage.

Helin Elhan, Justin L Korfhage, Thomas J Melia, Abdou Rachid Thiam.

The endoplasmic reticulum (ER) must carefully regulate the levels of nonmembrane lipids such as diacylglycerol (DAG), phosphatidic acid (PA), and triacylglycerol (TAG) to maintain membrane integrity and prevent lipotoxic stress. While ATG2A is well known as a lipid transfer protein essential for autophagosome formation, its role at lipid droplet (LD) contact sites has remained unclear. In our recent work, we show that ATG2A functions beyond its typical role in autophagy as a key regulator of lipid storage, transferring DAG, TAG, and PA from the ER to LDs and recruiting the TAG synthesis enzyme DGAT2 to promote LD expansion. Without ATG2A, lipids accumulate in the ER, leading to smaller, more numerous nucleated LDs rather than proper growth. Notably, ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis that prevents nonmembrane lipid accumulation in the ER. This cooperative process reveals ATG2A's dual role in both autophagy and lipid storage, highlighting an unexpected link between autophagy machinery and lipid storage.

Keywords: ATG2A; DGAT2; ER quality control; diacylglycerol; lipid droplets; lipid transfer

DOI: https://doi.org/10.1080/15548627.2026.2645161