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<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. 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. 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.</p>

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Naturally occurring ACE2 stalk variants are differentially released from the cell

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Florian Wiersch,
  • Christine Lux,
  • Julia Vanderliek-Kox,
  • Katharina Schun,
  • Andreas Ludwig,
  • Stefan Düsterhöft

摘要

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. 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. 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.