ABTB1, as an E3 ubiquitin ligase, suppresses Th17 cell differentiation and mitigates autoimmune inflammation by promoting STAT3 ubiquitination and degradation.

Proteins containing the broad-complex, tramtrack and bric-à-brac (BTB) domain, also referred to as the poxvirus and zinc finger (POZ) domain, play a variety of cellular roles. As key mediators of protein-protein interactions, these proteins participate in the regulation of various biological processes. In this study, we discovered that ankyrin repeat and BTB domain-containing protein 1 (ABTB1) acts as an important regulator of the differentiation of T helper 17 (Th17) cells. ABTB1 deficiency promotes Th17 cell differentiation and exacerbates the symptoms associated with dextran sodium sulfate (DSS)-induced colitis by enhancing Th17 cell-mediated inflammatory responses. Furthermore, the loss of ABTB1 decreases the polyubiquitination of signal transducer and activator of transcription 3 (STAT3) while increasing both the total expression and phosphorylation levels of the STAT3 protein, which are critical for Th17 cell differentiation. On a mechanistic level, this study provides the first evidence that neddylated ABTB1 functions as a novel E3 ubiquitin ligase. Neddylated ABTB1 mediates the K27-, K33-, and K48-linked polyubiquitination of STAT3, thereby promoting its degradation via the ubiquitin-proteasome pathway. Accordingly, ABTB1 inhibits the excessive activation of STAT3 and ultimately suppresses Th17 cell differentiation. Overall, our research demonstrates the critical role of ABTB1 in regulating the differentiation and function of Th17 cells under conditions of autoimmune diseases. Thus, ABTB1 may represent a potential therapeutic target for inflammatory bowel disease (IBD) and other autoimmune disorders.