Physiological role of Uev1a in lymphocytes and its implication in autoimmunity and lymphomagenesis

• Antragsteller: Professor Dr. Dirk Brenner
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2010 bis 2013
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 179852294

Protein ubiquitination has emerged as one of the key mechanisms regulating immune responses. Ubiquitination is the reversible, covalent addition of an ubiquitin molecule to a target protein such that the protein’s stability or activity are regulated. The importance of this pathway is highlighted by recent studies that link dysregulation of ubiquitination to the onset of autoimmunity and tumor development. A central factor in the ubiquitin signaling network is an E2 conjugating enzyme cofactor called “Ubc variant 1a” (Uev1a). Uev1a binds to Ubc13 to form an active E2 complex (Ubc13/Uev1a). In vitro studies have linked Uev1a to the activation of the NF-κB signaling pathway, implicating Uev1a in various receptor-induced cascades such as those involving the antigen receptors, the toll-like receptors (TLRs), CD40 or the interleukin (IL)-1 receptor. However, the role of Uev1a in vivo is still unclear. My proposed project aims to identify the physiological and pathological functions of Uev1a in lymphocytes, which are arguably the most important cells mediating the body’s immune responses to infections and incipient cancers. I propose to carry out conditional gene targeting of the murine genomic Uev1a locus such that Uev1a will be deleted specifically in the T or B lymphocytes of these mutant mice. The phenotypes of these animals and their lymphocytes will then be analyzed systematically in a multi-step process. First, the impact of Uev1a deficiency on T and B cell development and on major signaling cascades related to immune responses will be investigated. Because ubiquitination is crucial for the control of normal immunity, autoimmunity and tumorigenesis, I will elucidate the function of Uev1a in various disease models, including autoimmune-induced diabetes, experimental autoimmune encephalitis (EAE), and viral infection. The role of Uev1a in lymphomagenesis will be clarified in vivo through the use of an EμMYC mouse model as well as in a cell line-based model for diffuse large B cell lymphoma (DLBCL). For all these systems, the molecular mechanisms underlying any observed phenotypic abnormalities will be investigated in detail. Lastly, I will use a modified tandem affinity purification (moTAP) approach to identify molecular targets and/or Uev1a-interacting proteins, and will analyze their functions and expression with respect to the observed abnormal phenotypes. Given the central role of ubiquitination in intracellular signaling, the detailed in vivo analysis of a key cofactor such as Uev1a can only enhance our understanding of immune homeostasis.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: Kanada
• Gastgeber: Professor Dr. Tak Mak