Sunday, May 11, 2025
5/11/2025
Biological Mechanism of INF2-mediated FSGS - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).