Tension-induced autophagy: may the chaperone be with you

Abstract

Impairment of autophagy in patients and animal models severely affects mechanically strained tissues such as skeletal muscle, heart, lung and kidney, leading for example to muscle dystrophy, cardiomyopathy and renal injury. However, the reason for this high reliance on autophagy remained largely elusive. Recent work in our lab now provides a possible explanation. We identified chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway essential for mechanotransduction in mammalian cells.

Keywords: BAG3; CASA; Hsp70; WW domain; chaperone; mechanotransduction.

Figure 1. The CASA machinery integrates tension sensing, autophagosome formation and transcription regulation during mechanotransduction in mammalian cells. The machinery is localized at Z-disks in striated muscles and along actin stress fibers in smooth muscle and nonmuscle cells. A critical client of CASA is the actin-crosslinking protein FLN, which becomes unfolded and damaged under tension, leading to recognition and ubiquitination by the CASA complex. During FLN degradation autophagosome formation is triggered by the cooperation between BAG3, SYNPO2 and a VPS protein complex that facilitates the tethering and fusion of phagophores. BAG3 also uses its WW domain to contact LATS1/2 or AMOTL1/2, which are involved in the cytoplasmic sequestration of the transcription regulators YAP1 and WWTR1. BAG3 binding to LATS1/2 and AMOTL1/2 abrogates YAP1-WWTR1 sequestration and induces FLN transcription under tension. It remains to be elucidated whether BAG3 cooperates with HSPA8 and HSPB8 during transcription regulation. Ig, immunoglobulin-like; ECM, extracellular matrix.