|dc.description.abstract||Autophagy is a cellular process to sequester cytoplasmic components for delivery to lysosomes for subsequent degradation, and plays important roles in aging and aging-associated pathogenesis. MAP1S is a ubiquitously distributed autophagy activator, which directly binds to the autophagosome marker LC3, accelerates autophagy initiation and degradation. Elucidating the mechanism of MAP1S-mediated autophagy can generate insights to control aging and aging-associated diseases. We discover that the acetylation of MAP1S maintains the stability of MAP1S protein and promotes autophagy. MAP1S interacts with HDAC4 via an HDAC4-binding domain (HBD). HDAC4 destabilizes MAP1S via deacetylation and suppresses autophagic flux.
Huntington’s disease is a fatal progressive neurodegenerative disorder caused by the accumulation of aggregation-prone mutant Huntingtin protein (mHTT). Utilizing cell line stably expressing GFP-mHTT, we demonstrate that an overexpression of HDAC4 causes accumulation of mHTT aggregates by inhibiting MAP1S-mediated autophagy. Either suppression of HDAC4 or overexpression of HBD promotes the stability of MAP1S, and enhances MAP1S-regulated autophagic clearance of mHTT aggregates. This reveals a new potential strategy to treat Huntington’s disease by interrupting HDAC4-MAP1S interaction.
Spermidine is a polyamine that activates autophagy and enhances longevity in some model systems. MAP1S-mediated autophagy helps mice maintain their lifespans and suppresses diethylnitrosamine-induced hepatocellular carcinomas. Thus, we hypothesize that spermidine regulates MAP1S-mediated autophagy to prolong lifespans and suppress hepatocarcinogenesis. Our results indicate that spermidine activates autophagy by depleting cytosolic HDAC4 to reduce HDAC4-MAP1S interaction, and enhance the acetylation of MAP1S. Wild-type mice drinking spermidine-containing water have higher levels of MAP1S and autophagy activity, and extended lifespans, compared to wild-type mice drinking water; whereas MAP1S^-/- mice drinking spermidine have no significant increase in autophagy level and medium survival time, compared to MAP1S^-/- mice drinking water. Utilizing diethylnitrosamine-induced hepatocellular carcinoma mouse model, we find that spermidine enhances MAP1S to accelerate autophagic flux and suppress hepatocarcinogenesis in a MAP1S-dependent manner.
In sum, we uncover that HDAC4 deacetylates MAP1S, reduces the stability of MAP1S protein and impairs MAP1S-mediated autophagy. Blocking the association of MAP1S with HDAC4 leads to activation of MAP1S-mediated autophagy and suppression of aging and aging-associated diseases.||en