FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes

Area of Science:

• Cell Biology
• Genetics
• Nephrology

Background:

• Mutations in inverted formin-2 (INF2) are a common cause of autosomal dominant focal segmental glomerulosclerosis (FSGS).
• INF2 regulates actin dynamics and microtubule assembly, with disease-causing mutations typically found in its N-terminal region.
• The precise mechanism by which N-terminal INF2 mutations lead to FSGS has remained unclear.

Purpose of the Study:

• To investigate INF2 isoforms and cleavage in podocytes.
• To determine the role of INF2 cleavage in FSGS pathogenesis.
• To assess the impact of FSGS-associated mutations on INF2 fragment function.

Main Methods:

• Examined INF2 isoforms and cleavage in podocytes.
• Evaluated INF2 fragment expression in human kidney disease.
• Assessed the localization and function of INF2 N-terminal fragments, including the effect of the R218Q mutation.

Main Results:

• The INF2-CAAX isoform is predominant in podocytes; INF2 undergoes cathepsin-mediated cleavage, releasing the N-terminal DID fragment.
• The N-terminal fragment, normally in foot processes, mislocalizes with FSGS mutations; the C-terminal fragment localizes to the cell body.
• The N-terminal fragment promotes cell spreading in a cleavage-dependent manner, a function impaired by the R218Q mutation, but cleavage itself is unaffected.

Conclusions:

• INF2 cleavage generates independent N-terminal (DID) and C-terminal (DAD) fragments.
• This cleavage mechanism explains the localization of FSGS-associated mutations to the N-terminus.
• Impaired function of the released N-terminal fragment contributes to FSGS.