Regulated Intramembrane Proteolysis of ACE2: A Potential Mechanism Contributing to COVID-19 Pathogenesis?

Sandra M Gonzalez,Abu Bakar Siddik,Ruey-Chyi Su

doi:10.3389/fimmu.2021.612807

Sandra M Gonzalez, Abu Bakar Siddik + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2021.612807

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Abstract

Since being identified as a key receptor for SARS-CoV-2, Angiotensin converting enzyme 2 (ACE2) has been studied as one of the potential targets for the development of preventative and/or treatment options. Tissue expression of ACE2 and the amino acids interacting with the spike protein of SARS-CoV-2 have been mapped. Furthermore, the recombinant soluble extracellular domain of ACE2 is already in phase 2 trials as a treatment for SARS-CoV-2 infection. Most studies have continued to focus on the ACE2 extracellular domain, which is known to play key roles in the renin angiotensin system and in amino acid uptake. However, few also found ACE2 to have an immune-modulatory function and its intracellular tail may be one of the signaling molecules in regulating cellular activation. The implication of its immune-modulatory role in preventing the cytokine-storm, observed in severe COVID-19 disease outcomes requires further investigation. This review focuses on the regulated proteolytic cleavage of ACE2 upon binding to inducer(s), such as the spike protein of SARS-CoV, the potential of cleaved ACE2 intracellular subdomain in regulating cellular function, and the ACE2’s immune-modulatory function. This knowledge is critical for targeting ACE2 levels for developing prophylactic treatment or preventative measures in SARS-CoV infections.

Highlights

The recent pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARSCoV-2) has become a catastrophic event threating global health, reaching millions of infected individuals worldwide with a variable temporal estimates of case-fatality rate among the affected countries oscillating between 1.6% and 31.4% [1, 2] and requiring the establishment of repeated lockdowns in many countries to control the spreading and to reduce the impact of the infection
Several questions remain unsolved regarding Angiotensin converting enzyme 2 (ACE2) proteolysis during CoV infection, especially in SARS-CoV-2, including: 1) Is ACE2 cleavage triggered by SARS-CoV-2 infection? If so, 2) is ACE2 cleavage a regulated intramembrane proteolysis (RIP) event? 3) Are the extracellular and intracellular ACE2 subunits involved in regulation of cellular transcription, signaling and fate? 4) Is the exacerbated immune response and disease severity influenced by ACE2 proteolysis by a disintegrin and metallopeptidase 17 (ADAM17) or transmembrane protease serine 2 (TMPRSS2)? The answers to these questions could be key for understanding the immunopathogenesis of COVID-19 and for directing therapeutic approaches
Understanding the functional properties of these domains induced by coronavirus infection will enhance our knowledge in the pathogenesis, potentially mediated by ACE2 shedding and facilitate the design of preventative tools against a severe disease outcome

Summary

INTRODUCTION

The recent pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARSCoV-2) has become a catastrophic event threating global health, reaching millions of infected individuals worldwide with a variable temporal estimates of case-fatality rate among the affected countries oscillating between 1.6% and 31.4% [1, 2] and requiring the establishment of repeated lockdowns in many countries to control the spreading and to reduce the impact of the infection. Following CD147 shedding, its endodomain is released into cytosol and translocated to lysosomes to be cleaved again to produce a nuclear localizing subunit, which enhances autophagy function via the NF-kB–TRAIL–caspase8–ATG3 axis, favoring tumor cell survival [84] It remains to be explored if SARS-CoV-2 infection triggers RIP of CD147 and ACE2 to modulate cellular activity or function. Initial interaction between SARS-CoV-2 spike protein and the transmembrane cellular receptor ACE2 may trigger proteolytic cleavage of ACE2 mediated by ADAM17, releasing the extracellular domain of this receptor (ectodomain). Other proteases such as TMPRSS2, HAT and Hepsin may cleave ACE2 at a different catalytic site than ADAM17, potentially exhibiting differential outcomes. Several questions remain unsolved regarding ACE2 proteolysis during CoV infection, especially in SARS-CoV-2, including: 1) Is ACE2 cleavage triggered by SARS-CoV-2 infection? If so, 2) is ACE2 cleavage a RIP event? 3) Are the extracellular and intracellular ACE2 subunits involved in regulation of cellular transcription, signaling and fate? 4) Is the exacerbated immune response and disease severity influenced by ACE2 proteolysis by ADAM17 or TMPRSS2? The answers to these questions could be key for understanding the immunopathogenesis of COVID-19 and for directing therapeutic approaches

CONCLUSIONS

AUTHOR CONTRIBUTIONS