CCAR-1 affects hemidesmosome biogenesis by regulating unc-52/perlecan alternative splicing in the C. elegans epidermis
CCAR-1 affects hemidesmosome biogenesis by regulating unc-52/perlecan alternative splicing in the C. elegans epidermis
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CCAR-1 通过调节线虫表皮中的 unc-52/perlecan 选择性剪接影响半桥粒生物发生
DOI：
10.1242/jcs.214379
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发表时间：
2018-06-01
影响因子：
4
通讯作者：
Zhang, Huimin
中科院分区：
文献类型：
--
作者：
Fu, Rong;Zhu, Yi;Zhang, Huimin
摘要半桥粒是上皮细胞特有的附着结构，能维持组织的完整性和抵抗张力。尽管半桥粒很重要，但半桥粒如何在转录后水平上受到调控却知之甚少。秀丽线虫半桥粒(CeHD)具有与哺乳动物相似的结构和组成，使线虫成为研究半桥粒的理想模型。在这里，我们关注转录调节因子CCAR-1，它是在之前的基因筛查中发现的，目的是寻找保守的半桥粒成分VAB-10A(哺乳动物中称为plectin)突变的增强子。在VAB-10(E698)背景中CCAR-1功能的丧失会导致CeHD的破坏和肌肉从表皮上脱落。CCAR-1调控CeHD的生物发生，不是通过控制CeHD相关基因的转录，而是通过影响UNC-52(哺乳动物中称为perlecan或HSPG2)的选择性剪接，UNC-52是CeHD的基底细胞外基质(ECM)配体。CCAR-1与HRP-2(哺乳动物中的hnRNPR)在物理上相互作用，HRP-2是一种已知的剪接因子，介导UNC-52的选择性剪接，控制不同UNC-52亚型的比例，稳定CeHD。我们的发现强调了转录后调控在半桥粒重组中的重要性。它还揭示了CCAR-1在选择性剪接和半桥粒生物发生中先前未被认识的作用，为哺乳动物CCAR1在肿瘤发生中的作用机制提供了新的线索。摘要：线虫胚胎发生过程中CCAR-1功能的丧失导致UNC-52(哺乳动物Perlecan的同系物)选择性剪接失调和半桥粒破坏。
ABSTRACT Hemidesmosomes are epithelial-specific attachment structures that maintain tissue integrity and resist tension. Despite their importance, how hemidesmosomes are regulated at the post-transcriptional level is poorly understood. Caenorhabditis elegans hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making C. elegans an ideal model for studying hemidesmosomes. Here, we focus on the transcription regulator CCAR-1, identified in a previous genetic screen searching for enhancers of mutations in the conserved hemidesmosome component VAB-10A (known as plectin in mammals). Loss of CCAR-1 function in a vab-10(e698) background results in CeHD disruption and muscle detachment from the epidermis. CCAR-1 regulates CeHD biogenesis, not by controlling the transcription of CeHD-related genes, but by affecting the alternative splicing of unc-52 (known as perlecan or HSPG2 in mammals), the predicted basement extracellular matrix (ECM) ligand of CeHDs. CCAR-1 physically interacts with HRP-2 (hnRNPR in mammals), a splicing factor known to mediate unc-52 alternative splicing to control the proportions of different UNC-52 isoforms and stabilize CeHDs. Our discovery underlines the importance of post-transcriptional regulation in hemidesmosome reorganization. It also uncovers previously unappreciated roles of CCAR-1 in alternative splicing and hemidesmosome biogenesis, shedding new light on the mechanisms through which mammalian CCAR1 functions in tumorigenesis. Summary: Loss of CCAR-1 function during C. elegans embryogenesis results in dysregulated alternative splicing of unc-52 (the homolog of mammalian perlecan) and hemidesmosome disruption.