LC3A and Aggresomes: A trigger for UPR-activation, mitochondrial dysfunction, and cellular senescence

The protein quality control (PQC) network is crucial for maintaining cellular proteostasis by monitoring protein production, folding, and degradation. Unfolded protein response (UPR) and autophagy are key components of this network along with the compartmentalization of misfolded proteins into inclusion bodies. Among inclusion bodies, aggresomes, a bimolecular condensate, formed by collapsed vimentin cage surrounding misfolded/aggregated proteins at the microtubule organizing center. LC3A, a member of the LC3 family of autophagy-related proteins, has been implicated in regulating protein homeostasis. In this study, we investigated the role of LC3A in aggresome-positive cells. Expression of LC3A-mediated autophagy was associated with activation of the PERK-eIF2-ATF4 axis of the UPR and alterations in mitochondrial morphology. Prolonged expression of LC3A induced cellular senescence in aggresome-positive cells. These findings provide insights into the specialized role of LC3A in cellular homeostasis. Understanding the molecular mechanisms underlying LC3A-mediated autophagy has implications for therapeutic strategies targeting protein quality control pathways.