c9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.

c9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.
Autophagy. 2019 Dec 17;:
Authors: Shao Q, Yang M, Liang C, Ma L, Zhang W, Jiang Z, Luo J, Lee JK, Liang C, Chen JF
Abstract
How lysosome and MTORC1 signaling interact remains elusive in terminally differentiated cells. A G4C2 repeat expansion in C9orf72 is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS-FTD). We previously identified a C9orf72-SMCR8-containing complex. Here we found that c9orf72 and smcr8 double-knockout (dKO) mice exhibit similar but more severe immune defects than the individual knockouts. In c9orf72 or smcr8 mutant macrophages, lysosomal degradation and exocytosis were impaired due to the disruption of autolysosome acidification. As a result of impaired lysosomal degradation, MTOR protein was aberrantly increased, resulting in MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction, splenomegaly and lymphadenopathy in c9orf72 or smcr8 mutant mice. Pharmacological inhibition of lysosomal degradation upregulated MTOR protein and MTORC1 signaling in differentiated wild-type macrophages, which resemble phenotypes in KO mice. In contrast, C9orf72 or Smcr8 depletion in proliferating macrophages decreased MTORC1 signaling. Our studies causatively link C9orf72-SMCR8's cellular functions in lysosomal deg...

Source: Autophagy - December 16, 2019 Category: Cytology Authors: Shao Q, Yang M, Liang C, Ma L, Zhang W, Jiang Z, Luo J, Lee JK, Liang C, Chen JF Tags: Autophagy Source Type: research