These findings reveal that the levels of IL-23, IL-17, and IFN-gamma are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN-gamma is associated with the active intraocular inflammation in BD patients.

No abstract

The Chk1 protein is essential for genome integrity maintenance and cell survival in eukaryotic cells. After prolonged replication stress, Chk1 can be targeted for proteasomal degradation to terminate checkpoint signaling after DNA repair finishes. To ensure proper activation of DNA damage checkpoint and DNA repair signaling, a steady-state level of Chk1 needs to be retained under physiological conditions. Here, we report a dynamic signaling pathway that tightly regulates Chk1 stability. Under unperturbed conditions and upon DNA damage, ataxin-3 (ATX3) interacts with Chk1 and protects it from DDB1/CUL4A- and FBXO6/CUL1-mediated polyubiquitination and subsequent degradation, thereby promoting DNA repair and checkpoint signaling. Under prolonged replication stress, ATX3 dissociates from Chk1, concomitant with a stronger binding between Chk1 and its E3 ligase, which causes Chk1 proteasomal degradation. ATX3 deficiency results in pronounced reduction of Chk1 abundance, compromised DNA damage response, G2/M checkpoint defect and decreased cell survival after replication stress, which can all be rescued by ectopic expression of ATX3. Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance.

DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process. Here, we report that RBM45 can be recruited to laser microirradiation-induced DNA damage sites in a PAR- and FUS-dependent manner, but in a RNA-independent fashion. Depletion of RBM45 leads to abnormal DDR signaling and decreased efficiency in DNA double-stranded break repair. Interestingly, RBM45 is found to compete with histone deacetylase 1 (HDAC1) for binding to FUS, thereby regulating the recruitment of HDAC1 to DNA damage sites. A common familial ALS-associated FUS mutation (FUS-R521C) is revealed to prefer to cooperate with RBM45 than HDAC1. Our findings suggest that RBM45 is a key regulator in FUS-related DDR signaling whose dysfunction may contribute to the pathogenesis of ALS.