The role of ADAM17 during liver damage.

Mazin Al-Salihi,Karl S Lang,Anna Bornikoel,Yuan Zhuang,Pawel Stachura,Jürgen Scheller,Philipp A Lang

doi:10.1515/hsz-2021-0149

Abstract

A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.

Highlights

Chronic liver disease and liver damage are a major public health challenge, accounting for more than 1 million deaths worldwide annually (Byass 2014; Koyama and Brenner 2017)
epidermal growth factor receptor (EGFR) ligands can prevent liver damage and deletion of amphiregulin and heparinbinding-EGF-like growth factor (HB-EGF) can result in increased hepatocyte death and reduced proliferation
Administration of Hyper-IL-6 during toxic liver injury could alleviate liver damage and promote hepatocyte proliferation (Galun et al 2000). These findings suggest a prominent role of IL-6 trans-signaling, triggered by ADAM17 interleukin-6 receptor (IL-6R) cleavage, during liver regeneration

Summary

Introduction

Chronic liver disease and liver damage are a major public health challenge, accounting for more than 1 million deaths worldwide annually (Byass 2014; Koyama and Brenner 2017). Dimerization of ADAM17 with α5β1 integrin via its disintegrin domain has been suggested to promote the binding of active site tissue inhibitor of metalloproteinase 3 (TIMP3) (Wisniewska et al 2008), while decreasing the accessibility of the active site by steric hindrance (Bax et al 2004; Huang et al 2005) In addition to their role in trafficking ADAM17 from the ER to the Golgi, iRhoms have been demonstrated to play a role in the regulation of ADAM17 activation at the cell membrane, with ERK1/2-dependent phosphorylation of the cytoplasmic iRhom resulting in the release of mature ADAM17 and increased ADAM17 mediated shedding of TNFα (Adrain et al 2012; Grieve et al 2017; Maney et al 2015). ADAM17 dependent signaling is critical during liver damage and in liver disease (Table 1)

TNFα signaling

Viral hepatitis Liver regeneration

EGFR signaling

Other substrates

Concluding remarks