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MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake.
Quirin Emslander1, Karsten Krey1, Sabri Hamad1
1Institute of Virology, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany.
Viruses
|August 26, 2023
Summary
The E3 ligase MDM2 regulates Angiotensin-converting enzyme 2 (ACE2) stability, impacting SARS-CoV-2 entry. Lower MDM2 levels increase ACE2, enhancing viral infection.
Area of Science:
- Virology
- Molecular Biology
- Cellular Biology
Background:
- Angiotensin-converting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells.
- Host factors regulating ACE2 expression and localization are crucial for understanding SARS-CoV-2 infection dynamics.
- The precise mechanisms controlling ACE2 stability and their influence on viral infectivity remain incompletely understood.
Purpose of the Study:
- To investigate the role of host regulators, specifically the E3 ligase MDM2, in controlling ACE2 expression.
- To determine how MDM2-mediated regulation of ACE2 affects SARS-CoV-2 infection.
- To elucidate the molecular mechanism by which MDM2 influences ACE2 stability and viral uptake.
Main Methods:
- Genetic depletion of MDM2 in host cells.
- Assessment of ACE2 expression levels via quantitative assays.
- Infection studies using SARS-CoV-2 pseudotyped viruses and virus-like particles.
- Analysis of MDM2 ubiquitination of ACE2 at Lysine 788 and subsequent proteasomal degradation.
Main Results:
- Genetic depletion of MDM2 led to significantly elevated ACE2 expression levels.
- Increased ACE2 expression due to MDM2 depletion strongly promoted infection by various SARS-CoV-2 isolates.
- MDM2 was found to directly ubiquitinate ACE2 at Lysine 788, targeting it for proteasomal degradation, thereby controlling ACE2 stability and viral entry.
Conclusions:
- The E3 ligase MDM2 is a key regulator of ACE2 stability and expression.
- MDM2-mediated degradation of ACE2 plays a critical role in modulating SARS-CoV-2 infectivity.
- Cellular regulators like MDM2 are important determinants of host susceptibility to SARS-CoV-2.
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