Abstract
In bacterial and sterile inflammation of the liver, hepatocyte apoptosis is, in contrast to necroptosis, a common feature. The molecular mechanisms preventing hepatocyte necroptosis and the potential consequences of hepatocyte necroptosis are largely unknown. Apoptosis and necroptosis are critically regulated by the ubiquitination of signaling molecules but especially the regulatory function of deubiquitinating enzymes (DUBs) is imperfectly defined. Here, we addressed the role of the DUB OTU domain aldehyde binding-1 (OTUB1) in hepatocyte cell death upon both infection with the hepatocyte-infecting bacterium Listeria monocytogenes (Lm) and D-Galactosamine (DGal)/Tumor necrosis factor (TNF)-induced sterile inflammation. Combined in vivo and in vitro experiments comprising mice lacking OTUB1 specifically in liver parenchymal cells (OTUB1LPC-KO) and human OTUB1-deficient HepG2 cells revealed that OTUB1 prevented hepatocyte necroptosis but not apoptosis upon infection with Lm and DGal/TNF challenge. Lm-induced necroptosis in OTUB1LPC-KO mice resulted in increased alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release and rapid lethality. Treatment with the receptor-interacting serine/threonine-protein kinase (RIPK) 1 inhibitor necrostatin-1s and deletion of the pseudokinase mixed lineage kinase domain-like protein (MLKL) prevented liver damage and death of infected OTUB1LPC-KO mice. Mechanistically, OTUB1 reduced K48-linked polyubiquitination of the cellular inhibitor of apoptosis 1 (c-IAP1), thereby diminishing its degradation. In the absence of OTUB1, c-IAP1 degradation resulted in reduced K63-linked polyubiquitination and increased phosphorylation of RIPK1, RIPK1/RIPK3 necrosome formation, MLKL-phosphorylation and hepatocyte death. Additionally, OTUB1-deficiency induced RIPK1-dependent extracellular-signal-regulated kinase (ERK) activation and TNF production in Lm-infected hepatocytes. Collectively, these findings identify OTUB1 as a novel regulator of hepatocyte-intrinsic necroptosis and a critical factor for survival of bacterial hepatitis and TNF challenge.
Highlights
Upon exposure to pathogens and during inflammation, hepatocytes are sensitized to apoptosis but not necroptosis resulting in disturbance of liver function and potentially liver failure [1,2,3]
Upon binding of Tumor necrosis factor (TNF) to the TNF receptor 1 (TNFR1), a complex I consisting of TNFR1-associated via death domain (TRADD), TNFR-associated-factor (TRAF) 2/5, receptor-interacting serine/threonine-protein kinase (RIPK) 1, and cellular inhibitor of apoptosis-1 (c-IAP1) assembles
Inflammatory stimuli including TNF and pathogens can induce different types of cell death including apoptosis and necroptosis depending on the underlying cell type and the respective pathogen
Summary
Upon exposure to pathogens and during inflammation, hepatocytes are sensitized to apoptosis but not necroptosis resulting in disturbance of liver function and potentially liver failure [1,2,3]. Treatment with TNF or lipopolysaccharide (LPS) in combination with D-Galactosamine (D-Gal) mediates hepatocyte apoptosis and acute liver failure [15, 16]. In this model, D-Gal inhibits hepatocyte transcription and TNF signals through TNFR1 resulting activation of caspases and apoptosis of hepatocytes [15,16,17,18]. Based on the regulation of both cell death and proinflammatory signaling pathways by OTUB1 we explored the in vivo function of hepatocyte-specific OTUB1 during bacterial hepatitis and acute liver injury induced by DGal/ LPS and DGal/TNF. OTUB1 is an endogenous inhibitor of hepatocyte necroptosis and pro-survival factor during bacterial- and TNF-induced inflammation
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