- Open Access
Matrin 3 and HIV Rev Regulation of mRNA
© Dayton; licensee BioMed Central Ltd. 2011
- Received: 10 July 2011
- Accepted: 20 July 2011
- Published: 20 July 2011
The nuclear matrix protein, MATR3, is a newly-described Rev cofactor whose mechanism of action is only starting to be revealed.
- Polypyrimidine Tract
- Nuclear Matrix Protein
- Polypyrimidine Tract Binding
- Unspliced mRNA
- Typical mRNA
Retroviruses by necessity have evolved mechanisms to export unspliced viral genomic and mRNA out of the nucleus and into the cytoplasm, where they can be translated or assembled into virions. The first such system discovered was the Rev/Rev Response Element (RRE) system in HIV-1. The paradigm proposed for Rev/RRE function , whereby interaction of Rev with the RRE (originally known as CAR, for Cis Anti-Repressor) overcomes cis repressor sequences (CRS, or INS - inhibitory sequences) that otherwise retain unspliced/partially spliced mRNA within the nucleus, has proven remarkably durable. The early debates over whether Rev acts by splicing inhibition (allowing export) or by rapid export (kinetically outracing splicing and/or degradation), have devolved to a more complex picture, in which Rev interacts with the RRE and with CRM-1/exportin 1, which in turn interacts with the phenylalanine-glycine (FG) repeats of nucleoporins, mediating export. Once in the cytoplasm, Rev-dependent mRNAs, in some systems, may also require Rev for efficient translation (reviewed in ). Multiple factors have been reported to interact directly or indirectly with Rev-mediated mRNA transport/expression (reviewed in ). Furthermore, proposals for how CRS sequences block incompletely spliced viral RNA from productive export have invoked message instability, or message retention - the latter from suboptimal splicing or binding to nuclear factors (reviewed in ). Whatever the mechanisms involved, the effects of the Rev/RRE interaction are only apparent when the mRNA contains CRS/INS sequences.
Two papers recently co-published in this journal [5, 6] implicate the nuclear matrix protein, MATR3, as a co-factor used by the HIV-1 Rev protein to facilitate the nuclear export and translation of unspliced and partially spliced viral mRNA. The Marcello group came to this discovery using MS2 coat protein recognition sequence tags and MS2 pull down to survey host proteins specifically bound to HIV mRNA. The Jeang lab came to it through a yeast 2 hybrid survey of proteins that bound to PTB-1 ("polypyrimidine tract binding protein-1"), reasoning that, since PSF (a "PTB-1 associated splicing factor") inhibits the expression of CRS/INS-containing HIV-1 transcripts , other PTB-1 binding proteins, such as MATR3, might do so as well. Remarkably, these two divergent histories led to agreement on the facts at hand:
MATR3 binds intracellularly to HIV mRNA.
For maximal function, Rev needs MATR3 to promote the cytoplasmic accumulation and (presumably consequent) translation of unspliced (or partially spliced) RRE-containing mRNA.
Rev, MATR3 and RRE-containing mRNA form a detectable intracellular complex.
The addition of MATR3 to the pantheon of Rev cofactors is tantalizing: MATR3 exists in cells, complexed with PSF and nrbp54 [12–15]; PSF binds to CRS/INS sequences in HIV mRNA and suppresses the expression of these RNAs (); MATR3 has been identified as a constituent of the nuclear pore proteome . Consequently, it is tempting to view Rev as working with MATR3 to free mRNA from CRS retention (by, for example, PSF), allowing export; or as working with MATR3 to ferry mRNA to/through the nucleopore. The two mechanisms need not be mutually exclusive.
Finally, MATR3 has also been identified as interacting with the molecular chaperone cluster implicated by siRNA screening to be involved in viral assembly . This could underlie observations that Rev is involved in encapsidation (see  and ).
As is generally the case, the answers to all of these questions will emerge as more information is obtained concerning Rev/RRE and CRS/INS associated factors and their normal cellular roles. At the age of 24, the field of Rev remains rich and productive.
- Rosen CA, Terwilliger E, Dayton A, Sodroski JG, Haseltine WA: Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus. Proc Natl Acad Sci USA. 1988, 85: 2071-2075. 10.1073/pnas.85.7.2071.PubMed CentralView ArticlePubMedGoogle Scholar
- Groom HC, Anderson EC, Lever AM: Rev: beyond nuclear export. J Gen Virol. 2009, 90: 1303-1318. 10.1099/vir.0.011460-0.View ArticlePubMedGoogle Scholar
- Suhasini M, Reddy TR: Cellular proteins and HIV-1 Rev function. Curr HIV Res. 2009, 7: 91-100. 10.2174/157016209787048474.View ArticlePubMedGoogle Scholar
- Cochrane AW, McNally MT, Mouland AJ: The retrovirus RNA trafficking granule: from birth to maturity. Retrovirology. 2006, 3: 18-10.1186/1742-4690-3-18.PubMed CentralView ArticlePubMedGoogle Scholar
- Yedavalli VSRK, Jang K-T: Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression. Retrovirology. 2011, 8: 61-10.1186/1742-4690-8-S1-A61.PubMed CentralView ArticlePubMedGoogle Scholar
- Kula A, Guerra J, Knezevich A, Kleva D, Michael D, Myers P, Marcello A: Characterization of the HIV-1 RNA associated proteome identifies Matrin 3 as a nuclear cofactor of Rev function. Retrovirology. 2011, 8: 60-10.1186/1742-4690-8-S1-A60.PubMed CentralView ArticlePubMedGoogle Scholar
- Zolotukhin AS, Michalowski D, Bear J, Smulevitch SV, Traish AM, Peng R, Patton J, Shatsky IN, Felber BK: PSF acts through the human immunodeficiency virus type 1 mRNA instability elements to regulate virus expression. Mol Cell Biol. 2003, 23: 6618-6630. 10.1128/MCB.23.18.6618-6630.2003.PubMed CentralView ArticlePubMedGoogle Scholar
- Belgrader P, Dey R, Berezney R: Molecular cloning of matrin 3. A 125-kilodalton protein of the nuclear matrix contains an extensive acidic domain. J Biol Chem. 1991, 266: 9893-9899.PubMedGoogle Scholar
- Nakayasu H, Berezney R: Nuclear matrins: identification of the major nuclear matrix proteins. Proc Natl Acad Sci USA. 1991, 88: 10312-10316. 10.1073/pnas.88.22.10312.PubMed CentralView ArticlePubMedGoogle Scholar
- Hisada-Ishii S, Ebihara M, Kobayashi N, Kitagawa Y: Bipartite nuclear localization signal of matrin 3 is essential for vertebrate cells. Biochem Biophys Res Commun. 2007, 354: 72-76. 10.1016/j.bbrc.2006.12.191.View ArticlePubMedGoogle Scholar
- Zeitz MJ, Malyavantham KS, Seifert B, Berezney R: Matrin 3: chromosomal distribution and protein interactions. J Cell Biochem. 2009, 108: 125-133. 10.1002/jcb.22234.View ArticlePubMedGoogle Scholar
- Zhang Z, Carmichael GG: The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell. 2001, 106: 465-475. 10.1016/S0092-8674(01)00466-4.View ArticlePubMedGoogle Scholar
- Shav-Tal Y, Zipori D: PSF and p54(nrb)/NonO--multi-functional nuclear proteins. FEBS Lett. 2002, 531: 109-114. 10.1016/S0014-5793(02)03447-6.View ArticlePubMedGoogle Scholar
- Kameoka S, Duque P, Konarska MM: p54(nrb) associates with the 5' splice site within large transcription/splicing complexes. Embo J. 2004, 23: 1782-1791. 10.1038/sj.emboj.7600187.PubMed CentralView ArticlePubMedGoogle Scholar
- Buxade M, Morrice N, Krebs DL, Proud CG: The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008, 283: 57-65.View ArticlePubMedGoogle Scholar
- Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ: Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol. 2002, 158: 915-927. 10.1083/jcb.200206106.PubMed CentralView ArticlePubMedGoogle Scholar
- Bushman FD, Malani N, Fernandes J, D'Orso I, Cagney G, Diamond TL, Zhou H, Hazuda DJ, Espeseth AS, Konig R, et al: Host cell factors in HIV replication: meta-analysis of genome-wide studies. PLoS Pathog. 2009, 5: e1000437-10.1371/journal.ppat.1000437.PubMed CentralView ArticlePubMedGoogle Scholar
- Cockrell AS, van Praag H, Santistevan N, Ma H, Kafri T: The HIV-1 Rev/RRE system is required for HIV-1 5' UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles. Retrovirology. 2011, 8: 51-10.1186/1742-4690-8-51.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.