| First Author | Glynn RA | Year | 2024 |
| Journal | J Immunol | Volume | 213 |
| Issue | 5 | Pages | 628-640 |
| PubMed ID | 39007641 | Mgi Jnum | J:358829 |
| Mgi Id | MGI:7718563 | Doi | 10.4049/jimmunol.2300139 |
| Citation | Glynn RA, et al. (2024) ATM-dependent Phosphorylation of Nemo SQ Motifs Is Dispensable for Nemo-mediated Gene Expression Changes in Response to DNA Double-Strand Breaks. J Immunol 213(5):628-640 |
| abstractText | In response to DNA double-strand breaks (DSBs), the ATM kinase activates NF-kappaB factors to stimulate gene expression changes that promote survival and allow time for cells to repair damage. In cell lines, ATM can activate NF-kappaB transcription factors via two independent, convergent mechanisms. One is ATM-mediated phosphorylation of nuclear NF-kappaB essential modulator (Nemo) protein, which leads to monoubiquitylation and export of Nemo to the cytoplasm where it engages the IkappaB kinase (IKK) complex to activate NF-kappaB. Another is DSB-triggered migration of ATM into the cytoplasm, where it promotes monoubiquitylation of Nemo and the resulting IKK-mediated activation of NF-kappaB. ATM has many other functions in the DSB response beyond activation of NF-kappaB, and Nemo activates NF-kappaB downstream of diverse stimuli, including developmental or proinflammatory stimuli such as LPSs. To elucidate the in vivo role of DSB-induced, ATM-dependent changes in expression of NF-kappaB-responsive genes, we generated mice expressing phosphomutant Nemo protein lacking consensus SQ sites for phosphorylation by ATM or related kinases. We demonstrate that these mice are viable/healthy and fertile and exhibit overall normal B and T lymphocyte development. Moreover, treatment of their B lineage cells with LPS induces normal NF-kappaB-regulated gene expression changes. Furthermore, in marked contrast to results from a pre-B cell line, primary B lineage cells expressing phosphomutant Nemo treated with the genotoxic drug etoposide induce normal ATM- and Nemo-dependent changes in expression of NF-kappaB-regulated genes. Our data demonstrate that ATM-dependent phosphorylation of Nemo SQ motifs in vivo is dispensable for DSB-signaled changes in expression of NF-kappaB-regulated genes. |
