Abstract
Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days). However, several hundred fold increased production of type I collagen is often seen in reparative or reactive fibrosis. The mechanism which is responsible for this dramatic upregulation is complex, including multiple levels of regulation. However, posttranscriptional regulation evidently plays a predominant role. Posttranscriptional regulation comprises processing, transport, stabilization and translation of mRNAs and is executed by RNA binding proteins. There are about 800 RNA binding proteins, but only one, La ribonucleoprotein domain family member 6 (LARP6), is specifically involved in type I collagen regulation. In the 5′untranslated region (5’UTR) of mRNAs encoding for type I and type III collagens there is an evolutionally conserved stem-loop (SL) structure; this structure is not found in any other mRNA, including any other collagen mRNA. LARP6 binds to the 5′SL in sequence specific manner to regulate stability of collagen mRNAs and their translatability. Here, we will review current understanding of how is LARP6 involved in posttranscriptional regulation of collagen mRNAs. We will also discuss how other proteins recruited by LARP6, including nonmuscle myosin, vimentin, serine threonine kinase receptor associated protein (STRAP), 25 kD FK506 binding protein (FKBP25) and RNA helicase A (RHA), contribute to this process.
Highlights
Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days)
This suggested that binding of La ribonucleoprotein domain family member 6 (LARP6) to collagen α2(I) mRNA is more stable under competitive conditions that normally exist in the cell
These results suggested that translation of type I collagen mRNAs must be limited to allow coordination of production of α1(I) and α2(I) polypeptides and that recruitment of serine threonine kinase receptor associated protein (STRAP) is necessary for secretion of normal procollagen heterotrimer
Summary
Fibrotic diseases are characterized by excessive and uncontrolled synthesis of extracellular matrix proteins [1,2,3,4,5]. Type I collagen represents 80%–90% of the proteins in the fibrotic matrix and deposition of type I collagen fibrils disrupts normal tissue architecture, leading to loss of function [6]. Type III collagen is another fibrilar collagen present in the matrix, but it is a minor component and forms thin fibrils [7,8,9]. Other fibrilar collagens (type V, XI, XXIV and XXVII) are present in tracing amounts and type II collagen is not found in the fibrotic matrix. Understanding the molecular mechanism leading to excessive synthesis of type I collagen would greatly help discovery of specific antifibrotic drugs
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