Hemicentin mediated type IV collagen assembly strengthens juxtaposed basement membrane linkage

Basement membrane (BM) matrices surround and separate most tissues. However, through poorly understood mechanisms, BMs of adjacent tissues can also stably link to support organ structure and function. Using endogenous knock-in fluorescent proteins, conditional RNAi, optogenetics, and quantitative live imaging, we identified matrix proteins mediating a BM linkage (B-LINK) between the uterine utse and epidermal seam cell BMs in Caenorhabditis elegans that supports the uterus during egg-laying. We found that hemicentin is secreted by the utse and promotes fibulin-1 assembly to jointly initiate the B-LINK. During egg-laying, however, both proteins decline in levels and are not required for B-LINK maintenance. Instead, we discovered that hemicentin also promotes type IV collagen assembly, which accumulates to high levels during egg-laying and sustains the B-LINK during the mechanically active egg-laying period. This work reveals mechanisms underlying BM-BM connection maturation and identifies a crucial function for hemicentin and fibulin-1 in initiating attachment and type IV collagen in strengthening this specialized form of tissue linkage.

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Macromolecular constituents of basement membranes: a review of current knowledge on their structure and function

Canadian Journal of Biochemistry and Cell Biology ◽

10.1139/o83-120 ◽

1983 ◽

Vol 61 (8) ◽

pp. 942-948 ◽

Cited By ~ 15

Author(s):

Paul G. Scott

Keyword(s):

Type Iv Collagen ◽

Current Knowledge ◽

Heparan Sulphate ◽

Structural Features ◽

Structure And Function ◽

Basement Membranes ◽

Type Iv ◽

Type V ◽

And Function ◽

Additional Form

Macromolecules which appear to be integral constituents of basement membranes include type IV collagen, the glycoprotein laminin, and heparan sulphate proteoglycan. Another glycoprotein, fibronectin, may occupy an intermediate position between some lining cells and their basement membranes but is not, however, restricted to this location. An additional form of collagen, genetic type V which differs significantly from type IV collagen in structure, appears to be associated with some basement membranes, possibly linking them to underlying connective tissue. The main structural features of each of these macromolecules, as presently understood, are reviewed here as a background to the experimental papers in this "mini-symposium."

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Genetic Basis of Type IV Collagen Disorders of the Kidney

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.19171220 ◽

2021 ◽

pp. CJN.19171220

Author(s):

Catherine Quinlan ◽

Michelle N. Rheault

Keyword(s):

Basement Membrane ◽

Glomerular Basement Membrane ◽

Genetic Basis ◽

Type Iv Collagen ◽

Membrane Function ◽

Type Iv ◽

Filtration Barrier ◽

Membrane Structure And Function ◽

Wide Variability ◽

And Function

The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the α3(IV), α4(IV), and α5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and manipulation of collagen proteins.

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Dynamically remodeled hepatic extracellular matrix predicts prognosis of early-stage cirrhosis

Cell Death and Disease ◽

10.1038/s41419-021-03443-y ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Yuexin Wu ◽

Yuyan Cao ◽

Keren Xu ◽

Yue Zhu ◽

Yuemei Qiao ◽

...

Keyword(s):

Liver Cirrhosis ◽

Basement Membrane ◽

Type Iv Collagen ◽

Patient Survival ◽

Early Stage ◽

Ecm Remodeling ◽

Type Iv ◽

Ecm Proteins ◽

Stage Disease ◽

Cirrhotic Patients

AbstractLiver cirrhosis remains major health problem. Despite the progress in diagnosis of asymptomatic early-stage cirrhosis, prognostic biomarkers are needed to identify cirrhotic patients at high risk developing advanced stage disease. Liver cirrhosis is the result of deregulated wound healing and is featured by aberrant extracellular matrix (ECM) remodeling. However, it is not comprehensively understood how ECM is dynamically remodeled in the progressive development of liver cirrhosis. It is yet unknown whether ECM signature is of predictive value in determining prognosis of early-stage liver cirrhosis. In this study, we systematically analyzed proteomics of decellularized hepatic matrix and identified four unique clusters of ECM proteins at tissue damage/inflammation, transitional ECM remodeling or fibrogenesis stage in carbon tetrachloride-induced liver fibrosis. In particular, basement membrane (BM) was heavily deposited at the fibrogenesis stage. BM component minor type IV collagen α5 chain expression was increased in activated hepatic stellate cells. Knockout of minor type IV collagen α5 chain ameliorated liver fibrosis by hampering hepatic stellate cell activation and promoting hepatocyte proliferation. ECM signatures were differentially enriched in the biopsies of good and poor prognosis early-stage liver cirrhosis patients. Clusters of ECM proteins responsible for homeostatic remodeling and tissue fibrogenesis, as well as basement membrane signature were significantly associated with disease progression and patient survival. In particular, a 14-gene signature consisting of basement membrane proteins is potent in predicting disease progression and patient survival. Thus, the ECM signatures are potential prognostic biomarkers to identify cirrhotic patients at high risk developing advanced stage disease.

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