RESUMO
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. Caenorhabditiselegans 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.
Assuntos
Processamento Alternativo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Hemidesmossomos/metabolismo , Proteínas de Membrana/metabolismo , Proteoglicanas/metabolismo , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Epiderme/embriologia , Epiderme/metabolismo , Hemidesmossomos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Proteínas de Membrana/genética , Músculos/embriologia , Músculos/metabolismo , Ligação Proteica , Proteoglicanas/genéticaRESUMO
Spectraplakins are evolutionary conserved cytolinkers with characteristics of both the spectrin and the plakin family proteins. Caenorhabditis elegans possesses two categories of spectraplakin isoforms encoded by a single locus termed vab-10. Here we summarize the structure, homology, expression and functions of these spectraplakin family proteins in the nematode. We particularly focus on the diverse roles of VAB-10 isoforms in a number of organs and tissue types, as well as the similarities and distinctions of the underlying mechanisms. We also discuss the functional partners of VAB-10 in different contexts, plus the involvement of VAB-10 isoforms in physiological processes beyond cytoskeletal integration. We emphasize the importance of spectraplakin-related studies using Caenorhabditis elegans as the model, and their contributions to our understanding of spectraplakins across species.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Citoesqueleto/metabolismo , Proteínas dos Microfilamentos/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Genoma , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Modelos BiológicosRESUMO
The cell-cell and cell-ECM junctions within the epithelial tissues are crucial anchoring structures that provide architectural stability, mechanical resistance, and permeability control. Their indispensable role as signaling hubs orchestrating cell shape-related changes such as proliferation, differentiation, migration, and apoptosis has also been well recognized. However, growing amount of evidence now suggests that the multitasking nature of epithelial junctions extends well beyond anchorage-dependent or cell shape change-related biological processes. In this review, we discuss the emerging roles of junctional complexes in regulating innate immune defense, stress resistance, and intracellular proteostasis of the epithelial cells, with emphasis on the upstream regulation of epithelial junctions on various aspects of the epithelial barrier.
Assuntos
Células EpiteliaisRESUMO
Background: To evaluate the use of the diagnosis-related groups (DRGs) tool to promote the diagnosis/treatment ability and quality of the endocrinology department under the new policy of grouping payment-related to disease diagnosis. Methods: We compared the income structure of the endocrinology department in a 3a general hospital between the first half of 2019 and the same period in 2021. We also observed the changes in cost efficiency indexes (CEIs), time efficiency indexes (TEIs), case-mix index (CMI), number of DRGs, risk weight (RW) proportion, and surgery number in the inpatient department. Furthermore, the distribution of inpatients with diabetes of the whole hospital and the improvement of treatment efficiency indexes of the sub-specialty department were analyzed. Results: In the first half of 2021, compared with the same period of 2019, the total revenue of the endocrinology department decreased by 20.05%, the average hospitalization cost decreased by 11.72%, the CEI decreased from 1.31 to 1.06, and the TEI decreased from 0.74 to 0.64. Additionally, the number of DRGs increased from 162 to 176, the average CMI value increased from 0.80 to 0.84, and the proportion of RW 1-5 cases increased. Moreover, the number of surgical cases increased by 60.50%, minimally invasive surgery increased by 53.54%, grade 4 surgery increased by 66.67%, and the proportion of entering the clinical pathway increased from 77.76% to 86.64%. From May to August, 2021, the admission rate of endocrinology sub-specialty increased significantly, the number of DRGs showed an increasing trend, and the CEI and TEI decreased significantly. In the first half of 2021, inpatients with diabetes in the departments of rehabilitation, neurology, nephropathy, ophthalmology, and general administration accounted for 21.99-38.54%. Conclusions: The DRGs tool can be used to improve the clinical diagnosis and treatment ability of the endocrinology department, as well as optimize the CEI, TEI, CMI, and RW values. It is an effective way to promote the development of the endocrinology department under the new DRGs payment policy, carry out blood glucose management in the hospital, build endocrinology sub-specialties, and improve surgical and operation capacity.
RESUMO
A variety of disturbances such as starvation, organelle damage, heat stress, hypoxia and pathogen infection can influence the autophagic process. However, how the macroautophagy/autophagy machinery is regulated intrinsically by structural damage of the cell remains largely unknown. In this work, we utilized the C. elegans epidermis as the model to address this question. Our results showed that structural damage by mechanical wounding exerted proximal inhibitory effect and distant promotional effect on autophagy within the same epidermal cell. By disrupting individual mechanical supporting structures, we found that only damage of the basal extracellular matrix or the underlying muscle cells activated a distinct autophagic response in the epidermis. On the contrary, structural disruption of the epidermal cells at the apical side inhibited autophagy activation caused by different stress factors. Mechanistic studies showed that the basal promotional effect of structural damage on epidermal autophagy was mediated by a mechanotransduction pathway going through the basal hemidesmosome receptor and LET-363/MTOR, while the apical inhibitory effect was mostly carried out by activation of calcium signaling. Elevated autophagy in the epidermis played a detrimental rather than a beneficial role on cell survival against structural damage. The results obtained from these studies will not only help us better understand the pathogenesis of structural damage- and autophagy-related diseases, but also provide insight into more generic rules of autophagy regulation by the structural and mechanical properties of cells across species.Abbreviations : ATG: autophagy related; BLI-1: BLIstered cuticle 1; CeHDs: C. elegans hemidesmosomes; COL-19: COLlagen 19; DPY-7: DumPY 7; ECM: extracellular matrix; EPG-5: ectopic PGL granules 5; GFP: green fluorescent protein; GIT-1: GIT1 (mammalian G protein-coupled receptor kinase InTeractor 1) homolog; GTL-2: Gon-Two Like 2 (TRP subfamily); HIS-58, HIStone 58; IFB-1: Intermediate Filament, B 1; LET: LEThal; LGG-1: LC3, GABARAP and GATE-16 family 1; MTOR: mechanistic target of rapamycin; MTORC1: MTOR complex 1; MUP-4: MUscle Positioning 4; NLP-29: Neuropeptide-Like Protein 29; PAT: Paralyzed Arrest at Two-fold; PIX-1: PIX (PAK (p21-activated kinase) Interacting eXchange factor) homolog 1; RFP: red fluorescent protein; RNAi: RNA interference; SQST-1: SeQueSTosome related 1; UNC: UNCoordinated; UV: ultraviolet; VAB-10: variable ABnormal morphology 10; WT: wild type.
Assuntos
Autofagia , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Mecanotransdução Celular , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Epiderme/metabolismo , Células Epidérmicas/metabolismo , Mamíferos/metabolismoRESUMO
Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including MSH2, MSH6, PMS2, and MLH1. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the MSH2 gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of MSH2 exon 11, so that the predicted products of the mutant MSH2 mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that MSH2 mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the MSH2 gene causes LS and reaffirms the importance of genetic testing for LS.