Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

病毒性心肌炎是一种心肌炎症性疾病，是儿童与青年群体猝死的重要诱因。当前的新型冠状病毒肺炎（Coronavirus Disease 2019, COVID-19）大流行，进一步凸显了阐明病毒性心肌炎发病机制与潜在治疗策略的必要性。本研究发现，嗜心肌病毒可高度诱导TRIM29的表达，并在体外实验中促进蛋白激酶RNA样内质网激酶（protein kinase RNA-like endoplasmic reticulum kinase, PERK）介导的内质网（endoplasmic reticulum, ER）应激、细胞凋亡与活性氧（reactive oxygen species, ROS）应答，进而推动心肌细胞内的病毒复制。体内实验表明，TRIM29基因缺失可通过增强心脏抗病毒防御功能，抑制PERK介导的炎症反应与免疫抑制性单核细胞髓系来源抑制细胞（monocytic myeloid-derived suppressor cells, mMDSC），从而保护小鼠免受病毒性心肌炎的侵害。从机制层面而言，TRIM29可与PERK相互结合，促进PERK的SUMO化修饰（SUMOylation）以维持其蛋白稳定性，进而激活PERK介导的下游信号通路。本研究最终证实，PERK抑制剂GSK2656157可通过阻断TRIM29与PERK的相互作用，缓解病毒性心肌炎病情：具体表现为改善心脏功能、增强心脏抗病毒应答，并抑制体内炎症反应与免疫抑制性mMDSC的积累。本研究结果揭示了嗜心肌病毒通过调控TRIM29介导的PERK信号通路诱发病毒性心肌炎的分子机制，提示靶向TRIM29-PERK轴可有效减轻病毒性心肌炎的疾病严重程度。