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Background <p>Alternative splicing (AS) plays a crucial role in regulating protein function through the generation of structurally distinct isoforms.</p> Objective <p>We identify a novel splicing event in Chitinase 3-like 1 (CHI3L1) that modulates its secretion through conformational changes.</p> Methods <p>CHI3L1 alternative splicing was analyzed using the GTEx dataset. The regulation of CHI3L1 splicing was examined in response to THP-1 and BEAS-2B cells using RT-PCR. Structural modeling of CHI3L1 isoforms was conducted with AlphaFold to predict conformational changes caused by exon 8 exclusion. Protein expression and secretion levels of CHI3L1 isoforms were analyzed by Western blotting.</p> Results <p>Analysis of the GTEx dataset revealed tissue-specific regulation of CHI3L1 exon 8, with pronounced exclusion in lung tissue. The splicing pattern of CHI3L1 was dynamically regulated during THP-1 macrophage differentiation and by cell density in lung-derived epithelial BEAS-2B cells, suggesting its responsiveness to cellular context. While both full-length and exon 8-excluded CHI3L1 proteins showed cytoplasmic localization, structural analysis using AlphaFold revealed that exon 8 exclusion significantly altered the orientation of the signal peptide. Consequently, exon 8-excluded CHI3L1 exhibited minimal secretion into the culture medium compared to the full-length protein.</p> Conclusion <p>These findings demonstrate that alternative splicing-mediated exclusion of exon 8 serves as a novel regulatory mechanism controlling CHI3L1 secretion through conformational changes, providing new insights into the post-transcriptional regulation of secreted proteins.</p>

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Alternative splicing of CHI3L1 regulates protein secretion through conformational changes

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Haesoo Jung,
  • Yong-Eun Kim,
  • Eun-Mi Kim,
  • Kee K. Kim

摘要

Background

Alternative splicing (AS) plays a crucial role in regulating protein function through the generation of structurally distinct isoforms.

Objective

We identify a novel splicing event in Chitinase 3-like 1 (CHI3L1) that modulates its secretion through conformational changes.

Methods

CHI3L1 alternative splicing was analyzed using the GTEx dataset. The regulation of CHI3L1 splicing was examined in response to THP-1 and BEAS-2B cells using RT-PCR. Structural modeling of CHI3L1 isoforms was conducted with AlphaFold to predict conformational changes caused by exon 8 exclusion. Protein expression and secretion levels of CHI3L1 isoforms were analyzed by Western blotting.

Results

Analysis of the GTEx dataset revealed tissue-specific regulation of CHI3L1 exon 8, with pronounced exclusion in lung tissue. The splicing pattern of CHI3L1 was dynamically regulated during THP-1 macrophage differentiation and by cell density in lung-derived epithelial BEAS-2B cells, suggesting its responsiveness to cellular context. While both full-length and exon 8-excluded CHI3L1 proteins showed cytoplasmic localization, structural analysis using AlphaFold revealed that exon 8 exclusion significantly altered the orientation of the signal peptide. Consequently, exon 8-excluded CHI3L1 exhibited minimal secretion into the culture medium compared to the full-length protein.

Conclusion

These findings demonstrate that alternative splicing-mediated exclusion of exon 8 serves as a novel regulatory mechanism controlling CHI3L1 secretion through conformational changes, providing new insights into the post-transcriptional regulation of secreted proteins.