Mycobacterium tuberculosis phagosome Ca 2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages
Year: 2025
Type: article
Abstract: The role of canonical autophagy in controlling Mycobacterium tuberculosis (Mtb), referred to as xenophagy, is understood to involve targeting Mtb to autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca 2+ leakage after Mtb phagosome damage in human macrophages is the signal that triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target Mtb to lysosomes, excluding the canonical xenophagy. Upon Mtb phagosome damage, the Ca 2+ leakage–dependent ATG8/LC3 lipidation occurred on multiple membranes instead of single or double membranes excluding the noncanonical autophagy pathways. Mechanistically, Ca 2+ leakage from the phagosome triggered the recruitment of the V-ATPase–ATG16L1 complex independently of FIP200, ATG13, and proton gradient disruption. Furthermore, the Ca 2+ leakage–dependent ATG8/LC3 lipidation limited Mtb phagosome damage and restricted Mtb replication. Together, we uncovered Ca 2+ leakage as the key signal that triggers ATG8/LC3 lipidation on multiple membranes to mitigate Mtb phagosome damage.
Source: Science Advances
Institution: The Francis Crick Institute
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4408865491