USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

Abstract

USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866-1884).

Dual‐Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta–Activated Kinase 1 Suppression

“…Ubiquitin‐specific protease 18 interacted with TAK1 to suppress the activation of the c‐JNK and NF‐κB signaling pathways . TNF receptor–associated factor 3, binding to TAK1 to induce the ubiquitination and autophosphorylation of TAK1, regulated the IKKβ–NF‐κB and MKK–JNK–IRS1 signaling pathway to alleviate steatosis, insulin resistance, and systemic proinflammatory response in NAFLD . Tripartite motif containing 8 also participated in NASH and NAFLD by binding directly to TAK1, which activated the JNK–p38 and NF‐κB pathway .…”

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

“…[117][118][119] ASK1 is apical kinases in the MAPK pathways regulating the NF-κB pathway, mediated by p38 and JNK as well as MAPK kinase 4 (MKK4) and MKK7 while TAK1 can modulate PPARs via 5' adenosine monophosphate-activated protein kinase (AMPK) which is an important regulator in lipid metabolism. Cylindromatosis (CYLD), ubiquitin-specific protease 18 (USP18), and dual-specificity phosphatase 14 (DUSP14) are reported to be candidate enzymes for suppressing the progression of NASH via inhibiting TAK1, [92,[128][129][130] whereas the E3 ligase tripartite motif 8, TRAF3, promotes NASH. [120] TRAF1 and TRAF6 can be utilized to promote the activation of ASK1 whereas deubiquitinase TNFa-induced protein 3 (TNFAIP3), dickkopf-3 (DKK3), CASP8 and FADD-like apoptosis regulator (CFLAR), cellular repressor of E1A-stimulated genes (CREG) and caspase recruitment domain 6 can suppress ASK1 activation, which improves the NASH.…”

Versatility of USP18 in physiology and pathophysiology

“…Ubiquitin-specific peptidase 18 (USP18) is a cysteine protease of a dual nature. As an enzyme, it cleaves ubiquitin-like molecules (Ubls) from their target proteins, while as a substrate for an interferon (IFN) receptor it acts as an IFN type I and III signalling suppressor (Hoeller et al, 2006;Manini at al., 2013;Hong et al, 2014;Ketscher & Knobeloch, 2015;Honke et al, 2016;Mac-Parland et al, 2016;An et al, 2017;Basters et al, 2017;Mustachio et al, 2017;Basters et al, 2018;Shaabani et al, 2018;Gu et al, 2019). These diverse functions make USP18 an interesting object for research and many studies describing this unique molecule have been published recently.…”

“…These diverse functions make USP18 an interesting object for research and many studies describing this unique molecule have been published recently. Among others, its contribution to cell signalling, response to viral and bacterial infections, development of several malignancies and development of autoimmune diseases have been described (Liu et al, 1999;Ritchie et al, 2004;Hoeller et al, 2006;Catic et al, 2007;Duex & Sorkin, 2009;François-Newton et al, 2011;Murray et al, 2011;Burkart et al, 2012;Guo et al, 2012;Yim et al, 2012;Coit et al, 2013;Honke et al, 2013;Hong et al, 2014;Zhang et al, 2015;Honke et al, 2016;Ying et al, 2016;An et al, 2017;Arimoto et al, 2017;Basters et al, 2017;Mustachio et al, 2017;Basters et al, 2018;Shaabani et al, 2018;Gu et al, 2019). USP18 was also found to serve as an inhibitor of cardiac remodelling (Ying et al, 2016).…”