{"doi":"10.1681/asn.2019050443","title":"FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes","abstract":"BACKGROUND: Mutations in the gene encoding inverted formin-2 (INF2), a member of the formin family of actin regulatory proteins, are among the most common causes of autosomal dominant FSGS. INF2 is regulated by interaction between its N-terminal diaphanous inhibitory domain (DID) and its C-terminal diaphanous autoregulatory domain (DAD). INF2 also modulates activity of other formins, such as the mDIA subfamily, and promotes stable microtubule assembly. Why the disease-causing mutations are restricted to the N terminus and how they cause human disease has been unclear. METHODS: We examined INF2 isoforms present in podocytes and evaluated INF2 cleavage as an explanation for immunoblot findings. We evaluated the expression of INF2 N- and C-terminal fragments in human kidney disease conditions. We also investigated the localization and functions of the DID-containing N-terminal fragment in podocytes and assessed whether the FSGS-associated R218Q mutation impairs INF2 cleavage or the function of the N-fragment. RESULTS: The INF2-CAAX isoform is the predominant isoform in podocytes. INF2 is proteolytically cleaved, a process mediated by cathepsin proteases, liberating the N-terminal DID to function independently. Although the N-terminal region normally localizes to podocyte foot processes, it does not do so in the presence of FSGS-associated INF2 mutations. The C-terminal fragment localizes to the cell body irrespective of INF2 mutations. In podocytes, the N-fragment localizes to the plasma membrane, binds mDIA1, and promotes cell spreading in a cleavage-dependent way. The disease-associated R218Q mutation impairs these N-fragment functions but not INF2 cleavage. CONCLUSIONS: INF2 is cleaved into an N-terminal DID-containing fragment and a C-terminal DAD-containing fragment. Cleavage allows the N-terminal fragment to function independently and helps explain the clustering of FSGS-associated mutations.","journal":"Journal of the American Society of Nephrology","year":2020,"id":75071,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.962,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392269,"name":"Justin Chun","orcid":"0000-0002-3820-7192","position":1,"is_corresponding":false},{"id":393887,"name":"Chandra Perez-Gill","orcid":null,"position":2,"is_corresponding":false},{"id":392270,"name":"Paul Yan","orcid":"0000-0001-6275-9635","position":3,"is_corresponding":false},{"id":281385,"name":"Isaac E. Stillman","orcid":"0000-0002-4224-5060","position":4,"is_corresponding":false},{"id":392271,"name":"Henry N. Higgs","orcid":"0000-0002-2917-9644","position":5,"is_corresponding":false},{"id":54021,"name":"Seth L. Alper","orcid":"0000-0002-6228-2512","position":6,"is_corresponding":false},{"id":392272,"name":"Johannes Schlöndorff","orcid":"0000-0002-9973-9731","position":7,"is_corresponding":false},{"id":54020,"name":"Martin R. Pollak","orcid":"0000-0002-2396-9725","position":8,"is_corresponding":false},{"id":392268,"name":"Balajikarthick Subramanian","orcid":"0000-0001-6807-0257","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:46:33.313355Z","pmid":"31924668","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}