# Biological Mechanism of INF2-mediated FSGS

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $417,454

## Abstract

SUMMARY
The goal of project is to understand the molecular mechanisms by which mutations in INF2 cause focal
segmental glomerulosclerosis (FSGS) in humans. More than 45 different FSGS-associated mutations have
been identified. A subset of people with FSGS-causing INF2 mutations also exhibit Charcot Marie Tooth
disease. INF2 is unique for a formin family member in that it accelerates both actin polymerization and
depolymerization. Formins can autoinhibit their own activity by an intramolecular interaction between two
domains, the N-terminal DID (diaphanous inhibitory domain) and the C-terminal DAD (diaphanous
autoregulatory domain). INF2 has two major splice variants, one of which is associated with the endoplasmic
reticulum, INF2-CAAX, and a second isoform, INF2-nonCAAX, that helps maintain Golgi integrity. INF2-CAAX
is the major podocyte isoform.
During the last period of this grant, we made significant progress in our understanding of both INF2 biology and
how INF2 function is altered by mutations. We now understand the role INF2 plays in organelle function, and
have a clearer understand of its role in regulating mitochondrial fission. We have identified a major mechanism
of inhibition of INF2 activity, an interaction with an endogenous protein complex (cyclase-associated protein
bound to actin that is post-translationally acetylated). We have also found that the INF2 protein undergoes
cleavage at a site between the N-terminal DID region and the C-terminus, containing the FH2 and DAD
regions, which may be important in regulating INF2 function and perhaps disinhibiting the functions of both
regions of the protein. We have found that INF2 undergoes a cleavage event that may be important in
regulating INF2 function The fact that in contrast to essentially all other actin regulatory proteins, INF2-DID
mutations are a relatively common form of inherited FSGS, suggests that INF2-DID possesses unique and
non-redundant functions in the podocyte. Our long-term goal is to understand these functions and, ultimately,
exploit them for therapeutic benefit.
We have four major goals: (1) Define the specific biochemical effects of FSGS-causing mutants. We will test
the effects of multiple FSGS mutants on the interaction of INF2 with the endogenous inhibitory complex and
examine INF2 mutant interactions with its binding partners; (2) Define INF2 function and mutation-mediated
dysfunction in cells. This includes examination of how INF2 mutations alter its regulation of mitochondrial
function; (3) Define the function of INF2 cleavage; (4) Use genetically engineered mice to better understand
INF2 function and mutation mediated dysfunction in vivo.

## Key facts

- **NIH application ID:** 10765611
- **Project number:** 5R01DK088826-13
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** HENRY N HIGGS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,454
- **Award type:** 5
- **Project period:** 2010-07-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765611

## Citation

> US National Institutes of Health, RePORTER application 10765611, Biological Mechanism of INF2-mediated FSGS (5R01DK088826-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765611. Licensed CC0.

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