Human RNF34 blocking peptide

Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord.

Viral infection triggers the formation of mitochondrial antiviral signaling protein (MAVS) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS-mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF34 regulates immunity and mitophagy by targeting MAVS. RNF34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG-I-like receptor (RLR)-mediated antiviral immunity. Moreover, RNF34 catalyzes the K27-/K29-linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP52-dependent autophagic degradation. Specifically, RNF34 initiates the K63- to K27-linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG-I stimulation. Notably, RNF34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF34-mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.