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<p>Human podocin and <i>C. elegans</i> MEC-2 belong to the stomatin protein superfamily. They share 49% identity and 91% similarity both in the evolutionary conserved PHB domain (123-284&#xa0;aa) and in the oligomerization region (273-351&#xa0;aa). Amino acid substitutions in these conserved regions can modify the podocin oligomerization and thus the pathogenicity of <i>trans-</i>associated <i>NPHS2</i> 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 <i>mec-2</i> 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 <i>mec-2</i> mutant worm by reexpressing podocin (383 aa). However, we did not detect any chemotaxis defects in <i>mec-2(u37)</i> null mutants nor in <i>mec-2(e75)</i> missense mutants. No mechanosensation rescue was achieved by MEC-2A, but with a 17,5&#xa0;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 <i>mec-2</i> mutants.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Tália Magdolna Keszthelyi,
  • Regina Légrádi,
  • Dóra Pálya,
  • Tímea Köles,
  • Ágnes Regős,
  • Dóra Karancsiné Menyhárd,
  • Kálmán Tory

摘要

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.