The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis

Abstract

Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

“…Ubiquitination is a vital mechanism that precisely modulates ASK1 activity, in which E3 ubiquitin ligases play a critical role in determining the ubiquitin linkage types of ASK1, thus modulating ASK1 activation or degradation . Our previous serial studies have shown that several ASK1 ubiquitination types involved in the pathogenesis of NASH had been identified, including Lys11‐, Lys29‐, Lys48‐, and Lys63‐linked ubiquitination . However, in this study, we identified a previously unknown ubiquitination types (Lys6‐linked) for ASK1.…”

“…Accumulating evidence has widely demonstrated that apoptosis signal‐regulating kinase 1 (ASK1) is a potent driver of the inflammatory and fibrogenic responses by activating the downstream c‐Jun N‐terminal kinase (JNK)1/2‐mitogen‐activated protein kinase 14(p38) signaling cascade during NASH development . Moreover, inhibition of ASK1 is sufficient to mitigate onset and progression of NASH, making ASK1 a promising therapeutic target in NASH.…”

“…E3 ubiquitin ligases play an important role in determining ASK1 ubiquitination types in a cell type– or stimulation‐dependent manner, thus modulating ASK1 activation or degradation . Our previous study has shown that nonproteolytic polyubiquitination (including Lys63‐, Lys29‐, and Lys11‐linked polyubiquitination) regulates ASK1 activation and contributes to the pathogenesis of NASH . However, key E3 ubiquitin ligase(s) involved in ASK1 ubiquitination‐dependent activation in NASH remain to be determined.…”

Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches

“…Then, this complex phosphorylates and activates p38 and JNK, resulting in increase of hepatocyte injury via the BAX-caspase pathway, impairment of hepatic insulin resistance via Ser307 phosphorylation of insulin receptor substrate, increase of hepatic inflammation via pro-inflammatory cytokine/chemokine production, and increase of hepatic fibrosis via collagen production (39, 40). Recent emerging evidence suggests that several ASK1-interacting proteins such as Dickkopf-3 (DKK3), CASP8 and FADD-like apoptosis regulator (CFLAR, known as cFlip), and TNFα-induced protein 3 (TNFAIP3, known as A20) represent attractive therapeutic targets for the prevention and treatment of NAFLD/NASH (41–43). Further understanding of molecular mechanisms underlying the regulation of ASK1 activity will provide opportunities to identify novel therapeutic targets and to develop promising therapeutic compounds for treatment of NAFLD/NASH.…”

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

“…During metabolic stress, such as an excess of fatty acids, aberrant activation of ASK1 can lead to phosphorylation of p38 and the c‐Jun N‐terminal kinase (JNK) mitogen‐activated protein kinase (MAPK) pathway, which in turn triggers inflammatory and lipotoxic signaling that fuel the pathophysiology of nonalcoholic fatty liver disease (NAFLD)/NASH. Diverse posttranslational modifications determine the active state of ASK1, among which polyubiquitination is critical for subsequent ASK1 phosphorylation and activation . In addition to Lys48‐linked ubiquitination that mediates the degradation of ASK1, our previous study revealed other types of ubiquitination (Lys63‐, Lys29‐, and Lys11‐linked ubiquitination) that do not accompany protein degradation also regulate ASK1 activity in NASH .…”