| First Author | Li Y | Year | 2021 |
| Journal | Blood | Volume | 138 |
| Issue | 23 | Pages | 2360-2371 |
| PubMed ID | 34255829 | Mgi Jnum | J:335034 |
| Mgi Id | MGI:7260022 | Doi | 10.1182/blood.2021011247 |
| Citation | Li Y, et al. (2021) DYRK1a mediates BAFF-induced noncanonical NF-kappaB activation to promote autoimmunity and B-cell leukemogenesis. Blood 138(23):2360-2371 |
| abstractText | 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)-kappaB-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-kappaB activation. Interestingly, B-cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-kappaB activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-kappaB pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis. |
