DYRK1a mediates BAFF-induced noncanonical NF-?B activation to promote autoimmunity and B-cell leukemogenesis.

B-cell-activating factor (BAFF) mediates B-cell survival and, when deregulated, contributes to autoimmune diseases and B-cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B-cell survival. ...
B-cell-specific DYRK1a deficiency causes peripheral B-cell reduction and ameliorates autoimmunity in a mouse model of lupus. An unbiased screen identified DYRK1a as a protein that interacts with TRAF3, a ubiquitin ligase component mediating degradation of the noncanonical nuclear factor (NF)-?B-inducing kinase (NIK). DYRK1a phosphorylates TRAF3 at serine-29 to interfere with its function in mediating NIK degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-?B activation. Interestingly, B-cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-?B activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-?B pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis.
Mesh Terms:
Animals, Autoimmune Diseases, Autoimmunity, B-Cell Activating Factor, B-Lymphocytes, Carcinogenesis, Cell Line, Tumor, Humans, Leukemia, B-Cell, Mice, Mice, Inbred C57BL, NF-kappa B, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases
Blood
Date: Dec. 09, 2020
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