No protein kinase has yet been reported to directly phosphorylate and regulate Hsc70 activity.ĭysregulation of CMA has been linked to neurodegeneration, cancer, aging, metabolic regulation, and T cell response (Kon 2011 Cuervo and Wong 2014 Schneider et al. The mechanistic regulation of CMA is not fully understood. Lysosomal associated membrane protein 2A (Lamp2a), a lysosomal receptor, mediates the translocation of CMA substrates into the lysosomal lumen, a process that is assisted by a luminal resident form of Hsc70 (Cuervo and Dice 1996 Agarraberes et al. The CMA substrate proteins are recruited to the lysosomes by heat shock protein family A (Hsp70) member 8 (Hsc70), which recognizes the KFERQ motifs and delivers the substrates to the lysosomal membrane (Chiang et al. The selectivity of CMA is due to the requirement for its substrates to contain the Lys-Phe-Glu-Arg-Gln (KFERQ) motif (Dice et al. 2014 Valdor 2014 Kaushik and Cuervo 2015 Park et al. CMA has been linked to many cellular processes, including metabolism, DNA repair, and T cell activation (Schneider et al. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.Ĭhaperone-mediated autophagy (CMA) is one of three types of autophagy and has been identified only in birds and mammals (Gough and Fambrough 1997). Importantly, we find that in the APP/PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. However, the mechanisms that regulate CMA are not fully understood. Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.
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