CCAR-1 affects hemidesmosome biogenesis by regulating unc-52 /perlecan alternative splicing in the C. elegans epidermis

• Published in: Journal of cell science Vol. 131; no. 11; p. jcs214379
• Main Authors: Fu, Rong, Zhu, Yi, Jiang, Xiaowan, Li, Yuanbao, Zhu, Ming, Dong, Mengqiu, Huang, Zhaohui, Wang, Chunxia, Labouesse, Michel, Zhang, Huimin
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 11.06.2018; Company of Biologists
• Subjects: Alternative Splicing; Animals; Biosynthesis; Caenorhabditis elegans - embryology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cellular Biology; Embryogenesis; Embryonic growth stage; Enhancers; Epidermis; Epidermis - embryology; Epidermis - metabolism; Eukaryotes; Evolution; Extracellular matrix; Gene regulation; Genetic screening; Hemidesmosomes; Hemidesmosomes - genetics; Hemidesmosomes - metabolism; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Homology; Isoforms; Life Sciences; Mammals; Membrane Proteins - genetics; Membrane Proteins - metabolism; Muscles; Muscles - embryology; Muscles - metabolism; Mutation; Nematodes; Perlecan; Post-transcription; Protein Binding; Proteoglycans - genetics; Proteoglycans - metabolism; Splicing; Splicing factors; Tumorigenesis; Alternative splicing; C. elegans; unc-52; Perlecan; CCAR1; Hemidesmosome
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.214379

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. hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making 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 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 (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 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.