A role for CASM in the repair of damaged Golgi architecture

The term CASM describes a process in which LC3 and other Atg8 proteins are covalently ligated to lipids in damaged endomembranes. While CASM is commonly described as a cytoprotective response to multiple types of membrane damage, the ways in which CASM helps cells maintain homeostasis are still unclear. Here, we show that CASM contributes to the maintenance or repair of Golgi apparatus architecture following the loss of TRIM46, a ubiquitin ligase with roles in microtubule organization. TRIM46-deficient cells were notable for enhanced TFEB-driven lysosomal biogenesis and Golgi ribbon fragmentation, with colocalization between the trans-Golgi marker TGN46 and the Atg8 proteins LC3B and GABARAP. Similar results were seen when Golgi architecture was disrupted by inhibitors of microtubule assembly or of vesicle trafficking. Further studies revealed that the Golgi atg8ylation seen in TRIM46 knockout cells was not degradative and mechanistically resembled CASM. Genetic inhibition of CASM in TRIM46-deficent cells reduced TFEB activation and exacerbated the Golgi morphology defects. Together, these studies reveal that lysosomal biogenesis and CASM are common features of a Golgi damage response, with CASM acting to preserve Golgi integrity.