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

TL;DR

A specific isoform of MEC-2 with a long C-terminal region is needed to restore touch sensation in C. elegans, showing that human podocin cannot replace it.

Contribution

The study identifies the MEC-2E isoform with a large C-terminal region as essential for rescuing mechanosensation in C. elegans.

Findings

The MEC-2E isoform with a large C-terminal region rescues mechanosensation defects in mec-2 mutants.

Truncating the large C-terminal region of MEC-2E abolishes its rescue effect.

Human podocin cannot rescue the mechanosensation defects of mec-2 mutants.

Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-10711-w.

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