THEME
Fibrogenesis
III. Posttranscriptional regulation of type I collagen

J. N. Lindquist, W. F. Marzluff, and B. Stefanovic

Department of Biochemistry and Biophysics and Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27514


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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 ~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.

translation; transcription; mRNA stability; collagen alpha 1(I); gene regulation


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ONE ASPECT OF REGULATION OF protein synthesis that is often overlooked is the rate of translation. The context of the initiation codon is important for efficient recruitment of the 40S ribosomal subunit. mRNAs that contain a strong "Kozak sequence," the preferred consensus sequence, are translated more efficiently than mRNAs that have a poor context for the translation initiation codon (14). Other potential modulators of the rate of translation of a particular mRNA include the codon utilization. mRNAs that utilize the common codons for a particular amino acid for which there are abundant tRNAs are translated more efficiently than those that utilize rare codons.

There is normally competition among the many mRNAs for the translation initiation factors, which clearly limit the translation process. Regulation of translation can then be accomplished by altering the efficiency of assembly of the initiation complex on the mRNA. The initiation of translation requires the recruitment of a number of translation initiation factors to the mRNA that in turn result in the recruitment of the 40S ribosomal subunit, followed by the initiator methionine tRNA. The formation of an initiation complex requires the recruitment of eIF4G to the mRNA, which in turn binds to eIF3 that recruits the 40S ribosomal subunit to the translation initiation codon. Efficient translation of an mRNA requires that it contain both a 5' 7-methylguanine (7mG) cap and a poly(A) tail, both of which are critical for efficient translation initiation (13, 20). A model of a translation complex is shown in Fig. 1 and described below.


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Fig. 1.   A model of mRNA binding proteins during translation. PABP, poly(A) binding protein.

eIF4G is an ~200-kDa protein that has multiple regions that aid in assembly of the initiation complex. It binds with eIF4e, a ~25-kDa polypeptide that binds the 7mG cap found at the 5' end of mRNAs. Surprisingly, it also interacts with the poly(A) binding protein (PABP)-poly(A) complex found at the 3' end of all mRNAs except histone mRNAs (26, 12). This results in a "circular" mRNA, and a complex containing eIF4G bound to eIF4e at the 5' cap and PABP bound to the poly(A) tail may be the physiological translation initiation complex in mammalian cells. eIF4A, a member of the RNA helicase superfamily, also binds with eIF4G, and the complex then can translocate down the mRNA to the initiation codon.

At least three different types of sequences can affect regulation of translation initiation on an mRNA. Proteins that bind specific sequences in the 5' untranslated region (UTR) can block the formation of the initiation complex containing the 40S ribosomal subunit, completely inhibiting translation (8). The best-studied example is the regulation of iron metabolism, in which the iron response element binding protein binds the iron response element in the 5' UTR of a group of mRNAs, including ferritin mRNAs. As a result, the ferritin mRNA is found in the cytoplasm not associated with the ribosomes.

Sequences in the 3' UTR of the mRNA can affect the rate of translation initiation of an mRNA. Although the biochemical details of the function of these sequences have not been determined, these sequences likely function by binding specific proteins (2, 31). The resulting protein-RNA complex may affect the interaction of PABP either with the poly(A) tail or with eIF4G. Alternatively, they could affect the interaction of eIF4e with the cap. The result is to modulate the rate of translation of specific subsets of mRNAs. An mRNA that is being efficiently translated has multiple ribosomes bound to the mRNA at any one time, with the ribosomes located 80-100 nt apart. Translation occurs at ~5 amino acids/s (15 nt/s), so that the time between ribosomes is ~6 s. An mRNA that is being translated inefficiently due to a low rate of translation initiation will have the ribosomes widely spaced and will have fewer ribosomes bound at any one time. The distribution of mRNAs on polyribosomes can be determined by sucrose gradient analysis of cytoplasmic polyribosomes. As the translation rate of an mRNA increases, the mRNA becomes associated with larger polyribosomes.

A third mechanism of regulation of translation utilizes small open reading frames (ORFs) in the 5' UTR to control the rate of translation initiation. About 10% of mRNAs, many of which are involved in regulation of cell growth, contain short ORFs in the 5' UTR. These upstream ORFs are often translated, and regulation of the termination of their translation affects the translation of the downstream ORF (7). In the extreme cases, translation of the upstream ORF in the mRNA is arrested, with the mRNA associated with a single ribosome. Only when the ribosome completes translation is initiation of the downstream AUG activated. The regulation of translation of these mRNAs is determined by the termination and release of the upstream ORF-bound ribosome.

It may take up to 30 min to transcribe, process, and transport the average-sized mRNA and several hours to accumulate high levels of an mRNA. Translational regulation allows the cell to rapidly respond to changes in the environment by altering the rate of synthesis of specific proteins. It is probable that there is a large number of mRNAs whose translation is regulated. For example, a broad screen in yeast comparing the changes in mRNAs with the changes in proteins demonstrated that at least 20% of the yeast mRNAs did not show parallel changes with protein levels (9). Since this screen only detected the most abundant proteins, it likely underestimates the number of yeast mRNAs that are translationally controlled. In the future, we expect to see many more examples of posttranscriptional regulation being quantitatively important in the determination of the rate of production of a protein.


    REGULATION OF MRNA DEGRADATION
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Despite the fact that most mRNAs decay via a common pathway (21), there is a wide range of half-lives for different mRNAs, ranging from minutes to hours. The stability of a particular mRNA is determined by cis elements, which may be present in the 5' UTR, the coding region, or in the 3' UTR (18). Regulation of the half-life of mRNAs is probably accomplished by alteration of factors that interact with specific sequences in the mRNA. A model for the regulation of mRNA degradation is presented in Fig. 2 and described below.


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Fig. 2.   A model of mRNA degradation.

The major strategies for degrading mRNAs are conserved from yeast to human. The most common decay pathway occurs as a result of shortening of the poly(A) tail. When the poly(A) tail reaches a critical minimal length, the PABP presumably is no longer bound, and the loss of PABP disrupts the circular mRNA structure described above. The mRNA is then decapped and becomes accessible to exonucleases that can degrade the mRNA 5' to 3'. There are also enzymes that can degrade the mRNA 3' to 5'. The rates of the initial steps in degradation of specific mRNAs can be modulated by cis and trans elements that specifically bind to regions in the mRNA and cause degradation of specific transcripts in response to certain stimuli. For example, AU-rich elements located in the 3' UTR of many mRNAs generally destabilize the mRNA by binding specific proteins (10, 16).

Since the normal location of an mRNA is on polyribosomes on which it is being actively translated, it is not surprising that the initial steps in mRNA decay occur while the mRNA is associated with polyribosomes. As a result, many mRNAs are stabilized by inhibitors of protein synthesis. Degradation of an mRNA requires several enzymatic processes: deadenylation, decapping, and exonuclease activity. Recent results have indicated that many of these activities may be contained in a single complex, termed the exosome, or degradosome (1). This complex may function in a manner similar to the proteosome complex for protein degradation.


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In eukaryotes, PABP prevents deadenylation by preventing the degradation machinery from interacting with the RNA. Thus any factors that affect the rate of deadenylation will alter the half-life of the mRNA. The stability of many mRNAs is regulated by sequences in their 3' UTRs and determined by proteins interacting with these sequences. Factors that bind the 3' UTR are logical candidates for also interacting with the PABP-poly(A) complex and affecting the rate of deadenylation. For example, the HuR family of proteins binds AU-rich elements in the 3' UTR, resulting in stabilization of the poly(A) tail and the mRNA, whereas hnRNPD (Auf1) binds the same sequences and destabilizes the mRNA. This may occur by a disruption of the PABP interaction with either eIF4G or the poly(A) tail of the transcript. The alpha -globin and collagen alpha 1(I) mRNAs are stabilized by complexes bound to the 3' UTR that contain alpha CP2. These complexes may interact with PABP and stabilize the binding of PABP to the poly(A) tail or eIF4G (5, 11, 17), resulting in an increased stability of the mRNAs.


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Decapping usually follows the loss of the poly(A) tail and is mediated by an enzyme found in the degradosome (1, 4). The decapping is thought to allow a 5' to 3' exonuclease (Xrn1 in yeast) to degrade the mRNA. An mRNA that has been deadenylated and decapped may be degraded by either or both 5' to 3' or 3' to 5' mechanisms. There is also evidence that degradation of some mRNAs is initiated with an endonucleolytic cleavage (4). Cleavage in the 3' UTR would effectively deadenylate the mRNA, whereas cleavage in the 5' UTR would effectively decap the mRNA. Once the initial cleavage occurs, then the exonucleases would rapidly complete the degradation of the mRNA. Factors binding specific sequences could either protect against or enhance specific cleavages, effectively regulating the mRNA half-life.


    POSTTRANSCRIPTIONAL REGULATION OF COLLAGEN MRNA
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Cirrhosis of all etiologies is characterized by increased type I collagen mRNA levels, resulting in overproduction of collagen and the development of fibrosis. Expression of reporter genes driven by the collagen alpha 1(I) promoter in transgenic mice showed that, to achieve expression similar to the endogenous gene in collagen-producing tissues, a transgene driven by the collagen promoter had to be present in multiple copies. These mice also overexpressed the transgene in tissues that normally produce a low level of collagen, suggesting that transcription alone is not sufficient for regulated expression (22).

Activated hepatic stellate cells (HSCs) are the predominant source of collagen in fibrotic liver (6). The transcriptional rate of collagen alpha 1(I) gene was increased only threefold in activated HSCs compared with quiescent HSCs, demonstrating that most of the regulation leading to the 60- to 70-fold increase in collagen mRNA was posttranscriptional (24). The half-life of the alpha 1(I) mRNA was increased ~16-fold in activated HSCs compared with quiescent HSCs, and it is likely that other steps in collagen expression are also regulated. A model for the regulation of collagen alpha 1(I) is presented in Fig. 3 and discussed below.


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Fig. 3.   A model of collagen alpha 1(I) mRNA interactions in quiescent and activated stellate cells.

The three collagen mRNAs, alpha 1(I), alpha 2(I), and alpha 1(III), which are coordinately upregulated in fibrosis, contain a stem-loop structure in the 5' UTR (Fig. 4) that encompasses the translation initiation codon (start) (30). The 5' stem loop folds into a higher-order structure with a bulged A nucleotide (23). The 5' stem loop has been well conserved in evolution, differing by only 2 nt among Xenopus, chicken, and human collagen mRNAs. The evolutionary conservation of this sequence suggests that it must have an important function.


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Fig. 4.   The 5' stem loop of collagen alpha 1(I) mRNA.

Sequences in the 3' UTR are also critical in the regulation of collagen mRNA half-life. We have shown that the protein alpha CP2, implicated in globin mRNA stabilization, binds to the C-rich sequence located 23 nt 3' to the stop codon of alpha 1(I) mRNA (24). Binding of alpha CP2 can be demonstrated only in cytoplasmic extracts of activated HSCs, in which the collagen mRNA is stable, and not in extracts of quiescent HSCs, although both cell types contain the protein as judged by Northwestern blot analysis. Mutation of the alpha CP2 binding site in a reporter mRNA that contains the 5' stem loop also decreased mRNA stability in HSCs (23). alpha CP2 belongs to the K-homology domain family of RNA binding proteins and shuttles between the nucleus and cytoplasm. Purified recombinant alpha CP2 binds avidly to the C-rich 30-nt sequence derived from the collagen alpha 1(I) mRNA 3' UTR. Change of a single C nucleotide within the binding site dramatically decreases the binding of recombinant protein (J. N. Lindquist, unpublished observations). Interestingly, alpha CP2 binds a similar C-rich sequence to stabilize the alpha -globin mRNA and binds the C-rich sequences in the 3' UTRs of 15-lipoxygenase and tyrosine hydroxylase mRNA (11). The reason why alpha CP2 does not bind collagen alpha 1(I) mRNA in quiescent HSCs is not clear and requires further study. It most likely involves a posttranslation modification of alpha CP2. Phosphorylation of alpha CP2 inhibits its binding to RNA (15), and several kinases have been recognized to phosphorylate the K-homologous domain type of proteins (27).

alpha CP2 and the 5' stem loop binding activities regulate stability of collagen mRNA, but, since in eukaryotic cells translation and mRNA stability are coupled, they may also regulate its translation. A role of alpha CP2 in stimulating translation of some viral mRNA has been documented, and alpha CP2 can interact with PABP, a known stimulator of translation initiation (29). Therefore, it is possible that alpha CP2 enhances translation of collagen alpha 1(I) mRNA as well as increasing its stability, essentially by the same mechanism.

We have also analyzed a regulatory role of the 5' stem loop in two experimental systems: in quiescent and culture-activated HSCs (23) and in fibroblasts cultured in a three-dimensional matrix (25). The 5' stem loop prevented expression of the reporter genes in quiescent HSCs but allowed for expression in activated HSCs. This inhibitory effect of the stem loop was in part mediated by a decreased half-life of the corresponding mRNAs. By culturing mouse fibroblasts within a three-dimensional matrix composed of type I collagen, the cells revert from an activated phenotype to a more quiescent phenotype and downregulate collagen alpha 1(I) mRNA (25). Similarly, activated HSCs reverse to a more quiescent phenotype when cultured in Matrigel or pure collagen type I gels. In the context of full-size collagen alpha 1(I) mRNA, the 5' stem loop was also required for accelerated decay of the mRNA in fibroblasts grown in the matrix. In activated HSCs, a cytosolic protein factor(s) of 120 kDa binds to the stem loop and requires the 7mG cap on the RNA for binding, consistent with this protein playing a role in promoting translation and/or stability of the mRNA. We do not know whether this complex directly interacts with the 7mG cap or with the cap binding protein eIF4E. In quiescent HSCs we could not detect any protein binding to the stem loop in vitro. The binding of this complex is also greatly reduced if the cells are cultured in three-dimensional matrix, in which there is little collagen mRNA and collagen synthesis. Thus if these cytoplasmic proteins are absent, as in quiescent HSCs, or reduced, as in fibroblasts grown in the gel, alpha 1(I) mRNA may be inefficiently translated and targeted for degradation. If they are present, as in activated HSCs and fibroblasts grown in plastic, the alpha 1(I) mRNA may be stabilized and directed for translation.

We have also detected a nuclear binding activity targeted to the collagen alpha 1(I) stem loop (25). Compared with the cytoplasmic binding protein, this activity does not require the presence of the 7mG cap for binding and it has a different electrophoretic mobility in native gels. The nuclear binding is inversely correlated with accumulation of collagen alpha 1(I) mRNA, suggesting that it may be a negative modulator of collagen alpha 1(I) mRNA expression acting at a nuclear step in mRNA metabolism. We have cross-linked a protein of 110 kDa to the 5' stem loop in nuclear extracts. Its relationship to the 120-kDa cytoplasmic cross-link is unclear. So it is likely that collagen alpha 1(I) mRNA is regulated by complex interactions with sequence-specific RNA binding proteins in both the nucleus, where the complexes act to block mRNA accumulation, and the cytoplasm, where they promote translation and stabilize the mRNA.

Subcellular targeting of collagen alpha 1(I) and alpha 2(I) mRNAs and their coordinate translation has not been studied in detail. Collagens are secreted proteins, and their translation is coupled to the export of the peptides into the endoplasmic reticulum. All collagen alpha 1(I) mRNA is associated with membrane-bound polysomes and is not found on free polysomes or in postpolysomal supernatant (unpublished observations). All three peptides initiate folding into the heterotrimer while still associated with polysomes on the endoplasmic reticulum (3, 28). When folding is initiated, the collagen trimer is released in the lumen of endoplasmic reticulum. Heat-shock protein HSP 47 is a chaperone for folding of collagen triple helix and is present in activated HSCs. This protein coimmunoprecipitates with the polysome-associated collagen alpha 1(I) chains, so it also targeted to the site of collagen translation (19). It is possible that the translation machinery specific for synthesis and assembly of collagen type I forms at the membrane of the endoplasmic reticulum and the 5' stem loop of collagen mRNAs and its cognate binding proteins may be required for formation of such synthetic machinery.


    FOOTNOTES

Article published online before print. See web site for date of publication(http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: B. Stefanovic, Dept. of Biochemistry and Biophysics and Medicine, 154 Glaxo Bldg. CB# 7038, UNC-Chapel Hill, Chapel Hill, NC 27514 (E-mail: lindyx3{at}med.unc.edu).


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