Chaperone-mediated autophagy regulates adipocyte differentiation

Abstract

Adipogenesis is a tightly orchestrated multistep process wherein preadipocytes differentiate into adipocytes. The most studied aspect of adipogenesis is its transcriptional regulation through timely expression and silencing of a vast number of genes. However, whether turnover of key regulatory proteins per se controls adipogenesis remains largely understudied. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation that, in response to diverse cues, remodels the proteome for regulatory purposes. We report here the activation of CMA during adipocyte differentiation and show that CMA regulates adipogenesis at different steps through timely degradation of key regulatory signaling proteins and transcription factors that dictate proliferation, energetic adaptation, and signaling changes required for adipogenesis.

Molecular mechanisms of perilipin protein function in lipid droplet metabolism

“…In addition to transcriptional regulation, perilipin levels can be regulated by protein degradation. Besides previously mentioned studies implicating proteasomal degradation in the regulation of PLIN2, more recent work from the Cuervo group implicates CMA as an important regulator of adipocyte differentiation and adipogenesis [110]. This study shows that inactivation of basal CMA, in mouse 3T3L1 cells and in vivo , leads to a blockage in adipocyte differentiation at an early commitment step, suggesting that removal of PLIN2 from the growing LD occurs via CMA and is required to progress to full differentiation and for PLIN2–to–PLIN1 exchange.…”

LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles

“…CMA contributes to the rhythmic removal of clock machinery proteins and to the circadian remodeling of a subset of the cellular proteome [ 79 ]. CMA plays an important role in adipogenesis through timely degradation of key regulatory signaling proteins and transcription factors that dictate proliferation, energetic adaptation, and signaling changes required for adipogenesis [ 31 ].…”

Chaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases

“…Elevated levels of LAMP‐2A were detected both at the cellular level and in mice, suggesting increased CMA activity. Among them, MYC and transforming growth factor‐β (TGFβ) were identified as the major CMA substrates during adipose differentiation 46 …”

“…Among them, MYC and transforming growth factor-β (TGFβ) were identified as the major CMA substrates during adipose differentiation. 46 CMA was found to be engaged in the self-renewal and differentiation of embryonic stem cells by regulating their metabolism. CMA degrades isocitrate dehydrogenases to reduce the generation of α-ketoglutarate, 66 which maintains the pluripotency of embryonic stem cells.…”

“…Normal proteins which contain KFERQ‐motif are folded to act as CMA substrates, thereby regulating the signaling pathways in which these proteins are involved 22,45 . For example, during adipogenesis, CMA degrades limiting proteins in multiple crucial steps to drive adipogenesis 46 …”