III. Posttranscriptional regulation of type I collagen

Abstract

There are several independent metabolic steps that determine the level of a protein in eukaryotic cells. The steady-state level of the mRNA encoding the specific protein is determined by rate of transcription, percentage of transcripts that are ultimately processed and transported to the cytoplasm, and half-life of the mRNA in cytoplasm. The amount of protein that accumulates from a particular transcript is influenced not only by the amount of mRNA present in the cytoplasm but also by the rate of translation of the mRNA and stability of the protein product. There is compelling evidence that the steady-state level of many proteins is regulated at multiple steps, and when there is a large change in the amount of either mRNA or protein it is likely that multiple steps in the metabolism of the mRNA and protein have been altered. In the case of type I collagen production in the fibrotic liver, recent work has shown that there is regulation of multiple steps resulting in an approximately 70-fold increase in collagen production by the hepatic stellate cells. In addition to the well-documented relatively small effect on transcription, there are effects on processing/transport of the mRNA, translation of the mRNA, and stability of the mRNA. Large changes of protein levels are produced by altering the rates or efficiency of multiple steps. The molecular details of some of these posttranscriptional regulatory events are currently being elucidated. Here we review the various potential steps for regulation in the synthesis of a protein and discuss how the synthesis of type I collagen may be regulated in the fibrotic liver.

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

“…It is expressed at high levels in skin, bones, and tendons, with a low expression in parenchymal organs. During fibrosis of soft tissues, type I collagen expression is highly up-regulated at both transcriptional and post-transcriptional levels (Stefanovic et al 1999(Stefanovic et al , 2002Lindquist et al 2000b). The 50-100-fold up-regulation of type I collagen expression and secretion in fibrosis is primarily due to a 16-fold increase in a1(I) mRNA stability and a threefold increase in the transcription rate of collagen genes (Stefanovic et al 1995(Stefanovic et al , 1999(Stefanovic et al , 2000Stefanovic and Brenner 2003;Lindquist et al 2004;Rippe and Stefanovic 2005).…”

“…For the highly structured 59 UTR, it is likely that eIF4A needs the activity of additional factors with helicase activity for efficient ribosomal scanning (Pelletier and Sonenberg 1985). RHA may be specifically recruited by the PCE elements to provide such activity (Lindquist et al 2000b).…”

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

“…Type I collagen consists of two α1(I) and one α2 (I) polypeptide chains encoded by the α1(I) and α2(I) genes, respectively, and synthesized at a 2:1 ratio. As mentioned before, the enhanced expression of type I collagen by activated HSCs is regulated at both the transcriptional and posttranscriptional levels (137). The production and stability of α1(I) collagen mRNA are highly increased in liver fibrosis.…”

“…Excessive deposition of ECM results from both increased synthesis and decreased degradation of collagens (99). Expression of type I collagen is regulated at both the transcriptional and posttranscriptional levels (137). Posttranscriptional regulation results in up to 20-fold increase in the half life of collagen α1(I) mRNA (138,139).…”

“…Posttranscriptional regulation results in up to 20-fold increase in the half life of collagen α1(I) mRNA (138,139). The production of type I collagen can be increased ~70 fold by activated HSCs (137). In addition, the degradation of ECM is down-regulated.…”