In selective autophagy, receptors are central for cargo selection and delivery.However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy.Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor.Here we report that tumor-suppressing ubiquitin ligase, HACE1, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1, thus accelerating cellular autophagic flux.Therefore, ubiquitin signaling could directly regulate selective autophagy through promoting physical interaction between autophagy receptors, suggesting a previously unappreciated mode of regulation for autophagy.Interestingly, the K48-linked polyUbiquitin chains that the E3 conjugates onto OPTN might predominantly target OPTN for autophagic degradation.By demonstrating that the E3-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, which are otherwise deficient in autophagy, our findings may open a new avenue for developing autophagy-targeted therapeutic intervention into cancer.