{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:08:37Z","timestamp":1777950517424,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,29]]},"group-title":"Molecular Biology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt","doi-asserted-by":"crossref","award":["01KI20207"],"award-info":[{"award-number":["01KI20207"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Faculty of the RWTH Aachen University","award":["691903-06\/19"],"award-info":[{"award-number":["691903-06\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin-aldosterone system (RAAS). It also acts as a receptor for SARS-CoV-2 and stabilises the B0AT1 amino acid transporter at the cell surface. Therefore, surface expression of ACE2 is crucial for these physiological processes. ACE2 is released as a soluble, catalytically active form, partly through ectodomain shedding. This process mainly involves the sheddases ADAM10 and ADAM17, but the exact regulatory mechanisms remain unclear.<\/jats:p>\n                <jats:p>We assessed 11 naturally occurring single-point mutations in the ACE2 stalk region. Most variants showed significantly reduced release compared to wild-type (WT) ACE2; however, the single point mutations P734L and G726R significantly increased their release. ACE2_P734L also exhibits higher surface expression, directly increasing the surface levels of B0AT1. Despite B0AT1 and ACE2 forming a tight tetrameric complex, this did not affect ACE2 shedding. This suggests that complex formation does not restrict sheddase access.<\/jats:p>\n                <jats:p>Overall, these data identify the ACE2 stalk region as a major determinant of shedding efficiency. Naturally occurring variants in this region can substantially affect the release of soluble ACE2, potentially contributing to interindividual differences that are relevant for pathophysiological processes.<\/jats:p>","DOI":"10.64898\/2026.04.27.721131","type":"posted-content","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:15:15Z","timestamp":1777511715000},"source":"Crossref","is-referenced-by-count":0,"title":["Naturally occurring ACE2 stalk variants are differentially released from the cell"],"prefix":"10.64898","author":[{"given":"Florian","family":"Wiersch","sequence":"first","affiliation":[{"name":"Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1305-4749","authenticated-orcid":false,"given":"Christine","family":"Lux","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Vanderliek-Kox","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5552-1036","authenticated-orcid":false,"given":"Katharina","family":"Schun","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8536-4986","authenticated-orcid":false,"given":"Andreas","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, 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