1. The role of ATG5 beyond Atg8ylation and autophagy
- Author
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Wang, Fulong, Trosdal, Einar S, Paddar, Masroor Ahmad, Duque, Thabata LA, Allers, Lee, Mudd, Michal, Akepati, Prithvi R, javed, Ruheena, Jia, Jingyue, Salemi, Michelle, Phinney, Brett, and Deretic, Vojo
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Rare Diseases ,Biodefense ,Infectious Diseases ,Genetics ,Emerging Infectious Diseases ,Tuberculosis ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Animals ,Mice ,Autophagy ,Autophagy-Related Protein 5 ,Mycobacterium tuberculosis ,Endosomal Sorting Complexes Required for Transport ,Lysosomes ,ATG5 ,Atg8ylation ,autophagy ,lysosomal damage ,secretion ,tuberculosis ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
ATG5 plays a pivotal role in membrane Atg8ylation, influencing downstream processes encompassing canonical autophagy and noncanonical processes. Remarkably, genetic ablation of ATG5 in myeloid cells leads to an exacerbated pathological state in murine models of tuberculosis, characterized by an early surge in mortality much more severe when compared to the depletion of other components involved in Atg8ylation or canonical autophagy. This study shows that in the absence of ATG5, but not other core canonical autophagy factors, endolysosomal organelles display a lysosomal hypersensitivity phenotype when subjected to damage. This is in part due to a compromised recruitment of ESCRT proteins to lysosomes in need of repair. Mechanistically, in the absence of ATG5, the ESCRT protein PDCD6IP/ALIX is sequestered by the alternative conjugate ATG12-ATG3, contributing to excessive exocytic processes while not being available for lysosomal repair. Specifically, this condition increases secretion of extracellular vesicles and particles, and leads to excessive degranulation in neutrophils. Our findings uncover unique functions of ATG5 outside of the autophagy and Atg8ylation paradigm. This finding is of in vivo relevance for tuberculosis pathogenesis as modeled in mice.Abbreviations: Atg5: autophagy related 5; ESCRT: endosomal sorting complex required for transport; EVPs: extracellular vesicles and particles; FPR1: formyl peptide receptor 1; LyHYP: lysosomal hypersensitivity phenotype; LysoIP: lysosome immunopurification; Mtb: Mycobacterium tuberculosis; ORF3a: open reading frame 3a protein; PDCD6IP/ALIX: programmed cell death 6 interacting protein; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, TFEB: transcription factor EB.
- Published
- 2024