INF2

INF2, or inverted formin-2, is a human gene that encodes a member of the formin family of actin-regulating proteins. The encoded protein participates in remodeling the actin cytoskeleton and contributes to cell shape, motility, and organelle dynamics in several cell types. INF2 localizes to the endoplasmic reticulum and to ER–mitochondria contact sites, where it influences actin dynamics that support mitochondrial fission and ER morphology. In kidney cells, particularly podocytes, INF2-mediated actin remodeling helps maintain the integrity of the glomerular filtration barrier.

Mechanistically, INF2 contains the conserved FH1 and FH2 domains that execute actin polymerization and elongation, as well as autoregulatory DID/DAD modules typical of diaphanous-related formins. Its activity can promote actin filament assembly in a profilin-dependent manner, and under certain conditions contribute to actin turnover or filament severing. Regulation occurs through intramolecular autoinhibition and through upstream signals such as Rho family GTPases, which modulate the DID–DAD interaction.

Clinical significance is primarily linked to INF2 variants associated with autosomal dominant focal segmental glomerulosclerosis (FSGS), a kidney disease characterized by proteinuria and progressive renal impairment. In some instances, INF2 mutations are reported in families with peripheral neuropathies such as Charcot–Marie–Tooth disease or with overlapping kidney–nerve phenotypes. The proposed pathogenic mechanism involves disturbed actin dynamics in podocytes, leading to foot process effacement and compromised glomerular filtration.

Overall, INF2 plays a multifaceted role in actin-based cytoskeletal remodeling, with particular importance in podocyte function and mitochondria-associated organelle dynamics.