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

Kindlin-3-IPRR, the FERMT3 long isoform with a 4-residue IPRR insert in the PH domain, is fully functional and enhances β2 integrin activation and neutrophil adhesion during stress myelopoiesis.

• Why it matters: Leukocyte adhesion deficiency syndrome type III involves FERMT3 mutations, and prior work suggested the IPRR-containing isoform was dysfunctional; this study addresses whether it actually supports adhesion under hematopoietic stress.
• What they did: The authors tested kindlin-3-IPRR function in activating β2 integrins, measured phospholipid binding and plasma-membrane association, and analyzed RNA-seq across neutropoiesis stages, including patient samples after G-CSF or HSCT.
• The result: The IPRR insert increased phospholipid binding and promoted plasma-membrane recruitment, with the short isoform enriched in neutrophil precursors and the long isoform enriched in HSCs and mature neutrophils; during G-CSF stress, the long isoform selectively rose in mature neutrophils alongside enhanced β2-integrin activation.

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