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The ubiquitination-dependent processing of NF-κB2 (also known as p100) is a critical step in the activation of the noncanonical NF-κB pathway. We investigated the molecular mechanisms regulating this process and showed that TRIM55 was the E3 ubiquitin ligase that mediated the ubiquitination of p100 and coordinated its processing. TRIM55 deficiency impaired noncanonical NF-κB activation and B cell function. Mice with a B cell–specific Trim55 deficiency exhibited reduced germinal center formation and antibody production. These mice showed less severe symptoms than those of control mice upon the induction of a systemic lupus–like disease, suggesting B cell–intrinsic functions of TRIM55 in humoral immune responses and autoimmunity. Mechanistically, the ubiquitination of p100 mediated by TRIM55 was crucial for p100 processing by VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome. Furthermore, we found that TRIM55 facilitated the interaction between TRIM21 and VCP as well as TRIM21-mediated K63-ubiquitination of VCP, both of which were indispensable for the formation of the VCP-UFD1-NPL4 complex and p100 processing. Together, our results reveal a mechanism by which TRIM55 fine-tunes p100 processing and regulates B cell–dependent immune responses in vivo, highlighting TRIM55 as a potential therapeutic target for lupus-like disease. Editor's summary: The noncanonical NF-κB pathway is important for antibody-based immune responses mediated by B cells. Lin et al. found that the E3 ubiquitin ligase TRIM55 was critical for the generation of the transcription factor p52 from its precursor p100, an essential step in the activation of noncanonical NF-κB signaling. TRIM55 mediated the ubiquitination of p100 and facilitated the formation of protein complexes that processed ubiquitinated p100 into p52. B cell–specific deficiency of TRIM55 impaired antibody production and germinal center formation but also protected mice from a systemic lupus-like disease. Thus, TRIM55 promotes the activity of the noncanonical NK-κB pathway and could be a potential target for the treatment of autoimmune diseases. —Wei Wong [ABSTRACT FROM AUTHOR]