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Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.

Publication ,  Journal Article
Liang, P; Zhang, Y; Wan, YCS; Ma, S; Dong, P; Lowry, AJ; Francis, SJ; Khandelwal, S; Delahunty, M; Telen, MJ; Strouse, JJ; Arepally, GM; Yang, H
Published in: Blood
January 25, 2024

Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), its identity, activation mechanism, and role in RBC biology and disease remain elusive. Here, we demonstrate that TMEM16F, the long-sought-after RBC CaPLSase, is activated by calcium influx through the mechanosensitive channel PIEZO1 in RBCs. PIEZO1-TMEM16F functional coupling is enhanced in RBCs from individuals with hereditary xerocytosis (HX), an RBC disorder caused by PIEZO1 gain-of-function channelopathy. Enhanced PIEZO1-TMEM16F coupling leads to an increased propensity to expose PS, which may serve as a key risk factor for HX clinical manifestations including anemia, splenomegaly, and postsplenectomy thrombosis. Spider toxin GsMTx-4 and antigout medication benzbromarone inhibit PIEZO1, preventing force-induced echinocytosis, hemolysis, and PS exposure in HX RBCs. Our study thus reveals an activation mechanism of TMEM16F CaPLSase and its pathophysiological function in HX, providing insights into potential treatment.

Duke Scholars

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

January 25, 2024

Volume

143

Issue

4

Start / End Page

357 / 369

Location

United States

Related Subject Headings

  • Phospholipid Transfer Proteins
  • Ion Channels
  • Immunology
  • Hydrops Fetalis
  • Humans
  • Female
  • Erythrocytes
  • Calcium
  • Anemia, Hemolytic, Congenital
  • 3213 Paediatrics
 

Citation

APA
Chicago
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Liang, P., Zhang, Y., Wan, Y. C. S., Ma, S., Dong, P., Lowry, A. J., … Yang, H. (2024). Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis. Blood, 143(4), 357–369. https://doi.org/10.1182/blood.2023021465
Liang, Pengfei, Yang Zhang, Yui Chun S. Wan, Shang Ma, Ping Dong, Augustus J. Lowry, Samuel J. Francis, et al. “Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.Blood 143, no. 4 (January 25, 2024): 357–69. https://doi.org/10.1182/blood.2023021465.
Liang P, Zhang Y, Wan YCS, Ma S, Dong P, Lowry AJ, et al. Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis. Blood. 2024 Jan 25;143(4):357–69.
Liang, Pengfei, et al. “Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.Blood, vol. 143, no. 4, Jan. 2024, pp. 357–69. Pubmed, doi:10.1182/blood.2023021465.
Liang P, Zhang Y, Wan YCS, Ma S, Dong P, Lowry AJ, Francis SJ, Khandelwal S, Delahunty M, Telen MJ, Strouse JJ, Arepally GM, Yang H. Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis. Blood. 2024 Jan 25;143(4):357–369.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

January 25, 2024

Volume

143

Issue

4

Start / End Page

357 / 369

Location

United States

Related Subject Headings

  • Phospholipid Transfer Proteins
  • Ion Channels
  • Immunology
  • Hydrops Fetalis
  • Humans
  • Female
  • Erythrocytes
  • Calcium
  • Anemia, Hemolytic, Congenital
  • 3213 Paediatrics