Cholesterol‐driven sequestration of RETREG1/FAM134B regulates ERphagy and STING1 innate immunity

The endoplasmic reticulum (ER) is a hub for several essential functions, including lipid metabolism, macroautophagy/autophagy, and innate immune signaling. Excess ER generated during a stress response is degraded by a selective type of autophagy known as ERphagy/reticulophagy. A recent study provides a mechanism by which cholesterol levels regulate ERphagy, STING1 activation, and cholesterol biosynthesis. Elevated ER cholesterol levels suppress ERphagy by reducing RETREG1/FAM134B interactions with the autophagy-related protein MAP1LC3/LC3 and the lysosomal protein LAMP2. The study shows that cholesterol directly binds to RETREG1 and SCAP, facilitating the formation of the RETREG1-SCAP complex. Sequestration of RETREG1 in this manner prevents it from performing its ERphagy functions. Furthermore, RETREG1 also interacts with STING1 and is important for its activation in response to viral infections. SCAP-RETREG1 complex formation also reduces the STING1 response. Thus, this study links lipid metabolism, innate immunity, and autophagy, emphasizing a central role for cholesterol in these processes.