LAUSR

Rab22a‐NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a‐NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52‐mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63‐linked ubiquitin chains on lysine112 of Rab22a‐NeoF1, which is responsible for the binding of Rab22a‐NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a‐NeoF1. PINK1 is able to phosphorylate Rab22a‐NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a‐NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a‐NeoF1. These findings reveal that the lysosomal degradation of Rab22a‐NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A‐NeoF1 fusion gene.