The MEC-2E isoform with a large C-terminal completely rescues the touch sensation defect of C. elegans

• Published in: Scientific reports Vol. 15; no. 1; pp. 26606 - 10
• Main Authors: Keszthelyi, Tália Magdolna, Légrádi, Regina, Pálya, Dóra, Köles, Tímea, Regős, Ágnes, Karancsiné Menyhárd, Dóra, Tory, Kálmán
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 631/337/1645/1946; Amino acids; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Chemoreception; Chemotaxis; Cholesterol; Efficiency; Evolutionary conservation; Functional transcript; Genotype & phenotype; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipids; Localization; Mec-2; Mechanosensation; Mechanotransduction; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Missense mutant; multidisciplinary; Mutation; Oligomerization; Pathogenicity; Phenotype; Phenotypes; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Science; Science (multidisciplinary); Touch; Worms; Mechanosensation; Functional transcript; Mec-2; Chemotaxis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-025-10711-w

Human podocin and C. elegans MEC-2 belong to the stomatin protein superfamily. They share 49% identity and 91% similarity both in the evolutionary conserved PHB domain (123-284 aa) and in the oligomerization region (273-351 aa). Amino acid substitutions in these conserved regions can modify the podocin oligomerization and thus the pathogenicity of trans- associated NPHS2 variants, known as interallelic interactions. The MEC-2A isoform was formerly considered to be the functional isoform and used to evaluate the effect of pathogenic podocin variants. The mec-2 mutant worms are mechanosensation deficient, and, as recently described, also chemosensation deficient. To study the interallelic interactions of podocin in vivo, we aimed to rescue the phenotype of the mec-2 mutant worm by reexpressing podocin (383 aa). However, we did not detect any chemotaxis defects in mec-2(u37) null mutants nor in mec-2(e75) missense mutants. No mechanosensation rescue was achieved by MEC-2A, but with a 17,5 kb genomic region and the MEC-2E isoform (1239 aa) with a large C-terminal. Truncating the last third of the large C-terminal abolished its rescue effect. In conclusion, the function of MEC-2 in mechanosensation requires a large C-terminal encoded by the MEC-2E isoform. Accordingly, human podocin cannot rescue the phenotype of mec-2 mutants.