HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression

• Published in: Cell death and differentiation Vol. 27; no. 9; pp. 2651 - 2667
• Main Authors: Liu, Jiali, Du, Shuya, Kong, Qiuyue, Zhang, Xiaojin, Jiang, Surong, Cao, Xiaofei, Li, Yuehua, Li, Chuanfu, Chen, Huaqun, Ding, Zhengnian, Liu, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 13/89; 13/95; 38/77; 631/250/1932; 64/60; 692/699/255; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase-11; Caspase-4; Cell Biology; Cell Cycle Analysis; Endothelial cells; Heat shock proteins; Hepatocytes; Hsp70 protein; Hydrolase; Life Sciences; Lipopolysaccharides; Liver; Liver diseases; Macrophages; Nuclear transport; Pyroptosis; Sepsis; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-0536-x

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 GSDMD Nterm (markers of pyroptosis) were greater in livers of Hspa12a −/− 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 GSDMD Nterm generation 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.