| First Author | Ding S | Year | 2023 |
| Journal | Cell Death Discov | Volume | 9 |
| Issue | 1 | Pages | 430 |
| PubMed ID | 38036512 | Mgi Jnum | J:343413 |
| Mgi Id | MGI:7565885 | Doi | 10.1038/s41420-023-01736-z |
| Citation | Ding S, et al. (2023) Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation. Cell Death Discov 9(1):430 |
| abstractText | ISGylation is a well-established antiviral mechanism, but its specific function in immune and tissue homeostasis regulation remains elusive. Here, we reveal that the RNA-binding protein RBM47 undergoes phosphorylation-dependent ISGylation at lysine 329 to regulate immune activation and maintain lung homeostasis. K329R knockin (KI) mice with defective RBM47-ISGylation display heightened susceptibility to LPS-induced acute lung injury and lung tumorigenesis, accompanied with multifaceted immunosuppression characterized by elevated pro-inflammatory factors, reduced IFNs/related chemokines, increased myeloid-derived suppressor cells, and impaired tertiary lymphoid structures. Mechanistically, RBM47-ISGylation regulation of the expression of TSC22D3 mRNA, a glucocorticoid-inducible transcription factor, partially accounts for the effects of RBM47-ISGylation deficiency due to its broad immunosuppressive activity. We further demonstrate the direct inhibitory effect of RBM47-ISGylation on TSC22D3 expression in human cells using a nanobody-targeted E3 ligase to induce site-specific ISGylation. Furthermore, epinephrine-induced S309 phosphorylation primes RBM47-ISGylation, with epinephrine treatment exacerbating dysregulated cytokine expression and ALI induction in K329R KI mice. Our findings provide mechanistic insights into the dynamic regulation of RBM47-ISGylation in supporting immune activation and maintaining lung homeostasis. |
