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Published on: March 19, 2014

FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress

Serena Lee1, Gulinare Halimu1, Madeleine Sophie Vidal2

  • 1University of Nevada, Reno, Reno, Nevada, United States.

Blood
|August 10, 2026
PubMed

Insights

Leukocyte Adhesion Deficiency type III (LAD-III) is linked to FERMT3 mutations. This study reveals the longer kindlin-3 isoform (kindlin-3-IPRR) is functional, enhancing neutrophil adhesion and potentially aiding hematopoietic recovery.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Leukocyte Adhesion Deficiency type III (LAD-III) results from FERMT3 gene mutations, impacting leukocyte function.
  • The FERMT3 gene produces two kindlin-3 protein isoforms: a standard short form and a longer variant (kindlin-3-IPRR) with an IPRR insert in the PH domain.
  • Previous research suggested kindlin-3-IPRR was dysfunctional in neutrophil adhesion.

Purpose of the Study:

  • To investigate the functional role of the kindlin-3-IPRR isoform in neutrophil adhesion and integrin activation.
  • To analyze the expression patterns of kindlin-3 isoforms during hematopoiesis and stress conditions.
  • To explore the implications of kindlin-3 splicing in hematopoietic stress and recovery.

Main Methods:

  • In vitro assays to assess phospholipid binding and integrin activation by kindlin-3 isoforms.
  • RNA sequencing analysis of neutropoiesis and hematopoietic stem cells (HSCs).
  • Comparative analysis of kindlin-3 splicing in neutrophils from healthy donors and patients undergoing stress myelopoiesis (G-CSF treatment, HSC transplantation).

Main Results:

  • Kindlin-3-IPRR is fully functional, enhancing β2 integrin activation and neutrophil adhesion.
  • The IPRR insert improves phospholipid binding and plasma membrane association of kindlin-3.
  • Differential expression of kindlin-3 isoforms observed: short isoform dominant in precursors, long isoform in HSCs and mature neutrophils, with selective upregulation of the long isoform during stress myelopoiesis.

Conclusions:

  • Kindlin-3-IPRR plays a significant role in promoting neutrophil adhesion and may be critical for rapid neutrophil mobilization.
  • Alternative splicing of FERMT3 dynamically regulates integrin activation and leukocyte adhesion during hematopoietic stress.
  • Kindlin-3 splicing alterations during stress myelopoiesis could serve as a marker for monitoring hematopoietic recovery post-HSC transplantation.

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