E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors

[Display omitted] •Rnf128 deficiency raises the risk of colitis and increases the tumor burden in CRC induced by AOM/DSS or APC mutation.•RNF128 interacts with IL-6Rα and gp130 and mediated their lysosomal degradation in an E3 ligase activity-dependent manner.•RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866.•Blocking STAT3 activation effectively reversed the high susceptibility of Rnf128-deficient mice to colitis. Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. To elucidate the function and mechanism of RNF128 in colitis and CRC. Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis. RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.