Journal
DEVELOPMENTAL CELL
Volume 56, Issue 16, Pages 2313-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2021.07.015
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Funding
- National Key R&D Program of China [2018YFC1003603, 2017YFA0506300]
- National Natural Science Foundation [31970693]
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This study revealed the function of Vac8/ARMC3 in anchoring PtdIns3-kinase at the PAS and its physiological significance in mammalian spermatogenesis with germ tissue-specific autophagic function. Deficiency of ARMC3 in mice resulted in male infertility due to impaired autophagic degradation of cytosolic ribosomes, leading to low energy levels of mitochondria and motionless flagella in spermatids.
How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy initiation through recruitment of PIK3C3-C1 to the phagophore assembly site (PAS). This recruitment is dependent on the palmitoylation of Vac8 and on its middle ARM domains for binding PIK3C3-C1. Vac8-mediated anchoring of PIK3C3-C1 promotes PtdIns3P generation at the PAS and recruitment of the PtdIns3P binding protein Atg18-Atg2. The mouse homolog of Vac8, ARMC3, is conserved and functions in autophagy in mouse testes. Mice lacking ARMC3 have normal viability but show complete male infertility. Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. These studies uncovered a function of Vac8/ARMC3 in PtdIns3-kinase anchoring at the PAS and its physical significance in mammalian spermatogenesis with a germ tissue-specific autophagic function.
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