HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression
HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression
复制标题
HSPA12A 通过 PGC-1α 依赖的酰氧酰水解酶表达抑制 caspase-11 介导的肝细胞焦亡，减轻脂多糖诱导的肝损伤
DOI：
10.1038/s41418-020-0536-x
复制
发表时间：
2020-04-24
影响因子：
12.4
通讯作者：
Liu, Li
中科院分区：
文献类型：
--
作者：
Liu, Jiali;Du, Shuya;Liu, Li
肝功能障碍与脓毒症患者的低生存率密切相关。Caspase-4/5/11对胞质脂多糖（LPS）的感知是脓毒症发展的主要驱动因素。对巨噬细胞和内皮细胞的研究表明，脂多糖被acyloxyacyl hydrolase （AOAH）灭活，导致Caspase-4/5/11对脂多糖脱敏。然而，对脓毒症期间肝细胞胞质脂多糖诱导的焦亡知之甚少。热休克蛋白12A （HSPA12A）是HSP70家族的新成员。在这里，我们报道LPS增加了肝细胞中的HSPA12A核易位，而敲除小鼠的HSPA12A （HSPA12A−/−）促进了LPS诱导的急性肝损伤。我们还注意到，与野生型对照相比，lps诱导的Caspase-11激活及其对气皮蛋白D （GSDMD）的裂解产生形成膜孔的GSDMDNterm（焦亡标志物）在hspa12a−/−小鼠的肝脏中更大。功能缺失和功能获得的研究表明，在LPS孵育后的原代肝细胞中，HSPA12A缺乏促进（而HSPA12A过表达抑制）胞内LPS积累、Caspase-11激活和gsdmdtergeneration。值得注意的是，lps诱导的AOAH表达被HSPA12A缺乏抑制，而AOAH过表达逆转了HSPA12A缺乏诱导的lps诱导和caspase -11介导的肝细胞焦亡。深入的分子分析表明，HSPA12A直接与过氧化物酶体增殖物激活受体γ共激活因子1α (PGC-1α)相互作用，增加其核易位，从而诱导AOAH表达，使细胞内LPS失活，最终抑制Caspase-11介导的肝细胞焦亡。综上所述，这些发现表明HSPA12A通过pgc -1α介导的AOAH表达抑制lps诱导的胞质肝细胞焦亡，从而起到抗lps诱导肝损伤的新作用。因此，靶向肝细胞HSPA12A是脓毒症患者肝损伤治疗的可行策略。
Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a−/−) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMDNterm(markers of pyroptosis) were greater in livers ofHspa12a−/−mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMDNtermgeneration in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients.