Lysosomal vesiculophagy terminates STING signalling

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens 1,2 . Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum (ER) to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation 3–6 . Although the molecular machinery of STING activation is extensively studied and defined 7 , the one underlying STING degradation has not yet been fully elucidated. Here we show an unanticipated mechanism termed “lysosomal vesiculophagy” dictates STING degradation. Airyscan super-resolution microscopy and correlative light/electron microscopy show that a cluster of STING-positive vesicles of an RE origin are directly encapsulated into lysosome. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport 8 , shows that the endosomal sorting complexes required for transport (ESCRT) is essential for the STING encapsulation into lysosome. Knockdown of Tsg101 and Vps4, components of ESCRT 9 , results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. STING undergoes ubiquitination at REs and degradation of STING requires the ubiquitin-binding domain of Tsg101, ensuring the selective degradation of activated STING. Our results reveal a novel mode of autophagy that prevents hyperactivation of innate immune signalling and provide insights into the ER-Golgi-REs-lysosomes pathway for degradation of transmembrane proteins.