title: Splice variant-specific cellular function of the formin INF2 in maintenance of Golgi architecture.
abstract: INF2 is a unique formin that can both polymerize and depolymerize actin filaments. Mutations in INF2 cause the kidney disease focal and segmental glomerulosclerosis. INF2 can be expressed as two C-terminal splice variants: CAAX and non-CAAX. The CAAX isoform contains a C-terminal prenyl group and is tightly bound to endoplasmic reticulum (ER). The localization pattern and cellular function of the non-CAAX isoform have not been studied. Here we find that the two isoforms are expressed in a cell type-dependent manner, with CAAX predominant in 3T3 fibroblasts and non-CAAX predominant in U2OS, HeLa, and Jurkat cells. Although INF2-CAAX is ER localized in an actin-independent manner, INF2-non-CAAX localizes in an actin-dependent meshwork pattern distinct from ER. INF2-non-CAAX is loosely attached to this meshwork, being extracted by brief digitonin treatment. Suppression of INF2-non-CAAX causes fragmentation of the Golgi apparatus. This effect is counteracted by treatment with the actin monomer-sequestering drug latrunculin B. We also find discrete patches of actin filaments in the peri-Golgi region, and these patches are reduced upon INF2 suppression. Our results suggest that the non-CAAX isoform of INF2 serves a distinct cellular function from that of the CAAX isoform.
authors: Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
authors: Vinay
authors: V
authors: Ramabhadran
authors: Farida
authors: F
authors: Korobova
authors: Gilbert J
authors: GJ
authors: Rahme
authors: Henry N
authors: HN
authors: Higgs
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D000080865:Formins; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D041681:NIH 3T3 Cells; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D000080865:Formins; C546959:INF2 protein, human; C515509:INF2 protein, mouse; D008840:Microfilament Proteins; D020033:Protein Isoforms; D053778:Thiazolidines; C037068:latrunculin B