An investigation on proteolysis of the ACE2 receptor and its involvement in the cellular uptake and transmission of SARS-CoV-2

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dc.contributor.advisorMcCarthy, Justin V.en
dc.contributor.advisorLindsay, Andrewen
dc.contributor.advisorexternalColeman-Vaughan, Carolineen
dc.contributor.authorWakerlin, Samantha Leigh
dc.date.accessioned2022-01-27T15:45:54Z
dc.date.available2022-01-27T15:45:54Z
dc.date.issued2021-12-21
dc.date.submitted2021-12-21
dc.description.abstractThe renin-angiotensin system (RAS) is a key physiologic signalling network in blood and tissue homeostasis in humans. Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the protective axis in RAS signalling as it antagonises the mechanisms of Angiotensin II (Ang II), the major vasoactive peptide of the RAS that can be dysregulated and overactive in disease states. The type I transmembrane protein can also function as a viral receptor, as ACE2 has recently been identified as the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 undergoes ectodomain shedding by ADAM17 and other host cell proteases, resulting in the release of its catalytic ectodomain into the extracellular space and the C-terminal fragment (CTF) secured in the membrane. Ectodomain shedding is a prerequisite for further cleavage by gamma-secretase in a two-step mechanism known as regulated intramembrane proteolysis, a common fate of many known receptors that function as viral targets. Given the structural similarity of ACE2 to other known substrates of gamma-secretase, the hypothesised role of ACE2 as a substrate for the protease was explored. Here, we show that the ACE2 CTF product of ADAM17/TMPRSS2 shedding is subsequently cleaved by the gamma-secretase protease to produce an intracellular domain (ICD) that is released within the cell. Pharmacological inhibition of gamma-secretase prevents generation of the ACE2 ICD and leads to the accumulation of membrane-anchored ACE2 CTF lacking the catalytic ectodomain. These observations demonstrate that ACE2 is a substrate for gamma-secretase proteolysis, providing a novel pathway for cellular trafficking of ACE2 that may have therapeutic potential in protective RAS signalling or antiviral immunity.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationWakerlin, S. L. 2021. An investigation on proteolysis of the ACE2 receptor and its involvement in the cellular uptake and transmission of SARS-CoV-2. MRes Thesis, University College Cork.en
dc.identifier.endpage109en
dc.identifier.urihttps://hdl.handle.net/10468/12497
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2021, Samantha Leigh Wakerlin.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectACE2en
dc.subjectADAM17en
dc.subjectTMPRSS2en
dc.subjectGamma-secretaseen
dc.subjectSARS-CoVen
dc.subjectSARS-CoV-2en
dc.subjectCOVID-19en
dc.subjectAngiotensin-converting enzyme 2en
dc.subjectRegulated intramembrane proteolysisen
dc.titleAn investigation on proteolysis of the ACE2 receptor and its involvement in the cellular uptake and transmission of SARS-CoV-2en
dc.typeMasters thesis (Research)en
dc.type.qualificationlevelMastersen
dc.type.qualificationnameMRes - Master of Researchen
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