Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression
© Yedavalli and Jeang; licensee BioMed Central Ltd. 2011
Received: 16 February 2011
Accepted: 20 July 2011
Published: 20 July 2011
Post-transcriptional regulation of HIV-1 gene expression is mediated by interactions between viral transcripts and viral/cellular proteins. For HIV-1, post-transcriptional nuclear control allows for the export of intron-containing RNAs which are normally retained in the nucleus. Specific signals on the viral RNAs, such as instability sequences (INS) and Rev responsive element (RRE), are binding sites for viral and cellular factors that serve to regulate RNA-export. The HIV-1 encoded viral Rev protein binds to the RRE found on unspliced and incompletely spliced viral RNAs. Binding by Rev directs the export of these RNAs from the nucleus to the cytoplasm. Previously, Rev co-factors have been found to include cellular factors such as CRM1, DDX3, PIMT and others. In this work, the nuclear matrix protein Matrin 3 is shown to bind Rev/RRE-containing viral RNA. This binding interaction stabilizes unspliced and partially spliced HIV-1 transcripts leading to increased cytoplasmic expression of these viral RNAs.
The nucleus is a highly organized structure. Chromosomes occupy discrete regions, and specific proteins and nucleic acids are enriched in subnuclear structures such as nuclear lamina, nucleoli, Cajal bodies, nuclear speckles, and paraspeckles [1–6]. The nuclear matrix, a network of underlying filaments in the cell nucleus, shapes the nuclear architecture and functions in genome maintenance, transcription and RNA metabolism [7–17]. Accordingly, the nuclear matrix has important roles in tissue development and cellular proliferation; and the disruption of nuclear organization is often correlated with disease states such as the loss of subnuclear promyelocytic leukemia bodies in acute promyelocytic leukemia [18–21].
HIV-1 gene expression and replication are regulated at transcriptional and post-transcriptional steps including the transactivation of the HIV-1 LTR by Tat  and the export of unspliced or partially spliced viral RNAs from the nucleus to the cytoplasm by Rev [23–26]. Rev is a trans-acting viral protein which binds to a cis-acting Rev responsive element (RRE) present in unspliced and partially spliced HIV transcripts. Rev has been shown to interact with cellular proteins CRM1, DDX3, PIMT and others to mediate the export of unspliced and singly spliced viral RNAs [27–30]. The mechanism of viral RNA export by Rev is discrete from the export pathways used by fully spliced HIV-1 mRNAs, CTE- (constitutive transport element) dependent RNAs, and cellular mRNAs [31–43].
Recently, numerous studies have implicated the nuclear matrix in gene transcription, RNA splicing, and transport of cellular RNAs [5, 7, 9, 44, 45]; however, the role of the nuclear matrix in HIV-1 gene expression has been poorly explored [46–48]. Here, we identify Matrin 3 as a key component of factors that mediate the post-transcriptional regulation of HIV-1. Matrin 3 is a highly conserved inner nuclear matrix protein which has been previously shown to play a role in transcription [49–52]. It interacts with other nuclear matrix proteins to form the internal fibrogranular network; it acts in the nuclear retention of promiscuously A-to-I edited RNAs in cooperation with p54(nrb) and PSF [53, 54]; it participates in NMDA-induced neuronal death; it modulates the promoter activity of genes proximal to matrix/scaffold attachment region (MAR/SAR) ; and it is involved in the repair of double strand breaks . Our current findings implicate that Matrin 3 also influences the post-transcriptional expression of a subset of HIV-1 mRNAs.
Matrin 3 enhances Rev/RRE directed gene expression
List of Human and Mouse PTB-1 interacting proteins identified by yeast 2 hybrid assay.
PTB-1 interacting proteins identified by yeast 2 hybrid assay
A) Interacting with Human PTB-1
Calcium and integrin binding 1
CIB1; CIB; kinase-interacting protein 1; KIP1
Cleavage stimulation factor, 3' pre-RNA, subunit 2, 64 kD, tau
Homeodomain-interacting protein kinase 1 isoform1
poly(rC) binding protein 1
RNA binding motif protein 10
heterogeneous nuclear ribonucleoprotein K, isoform b
heterogeneous nuclear ribonucleoprotein L
A) Interacting with Mouse PTB-1
arylhydrocarbon receptor nuclear translocator
ARNT, hypoxia-inducible factor 1, beta subunit; dioxin receptor
Calcium and integrin binding 1
CIB1; CIB; KINASE-INTERACTING PROTEIN 1; KIP1
DAZ associated protein 2
nuclear receptor coactivator 6
RNA binding motif protein 10
protein BAT2-like 1
hexaribonucleotide binding protein 3
HRNBP3; RBFOX3; FOX3
G protein pathway suppressor 2
proline rich 3
tripartite motif-containing 8
zinc finger, CCHC domain containing 2
zinc finger protein 36, C3H type, homolog
ZFP36A, tristetraprolin; NUP475
neuro-oncological ventral antigen 1
neuro-oncological ventral antigen 2
We next investigated if Matrin 3 acts at steps post transcription. Rev is required for the cytoplasmic localization of unspliced and partially spliced HIV-1 mRNAs that encode for viral Gag, Env, Vif and Vpu proteins. Rev binds to an RRE-RNA motif in these RNAs [60, 61]. Unlike fully spliced viral RNAs, these transcripts contain cis-inhibitory RNA elements which restrict their export from the nucleus into the cytoplasm in the absence of Rev binding to the RRE motif. The binding of Rev to the RRE frees this restriction, and Gag protein expression is thus increased by several fold compared to its expression in the absence of Rev [60, 61].
We checked if Matrin 3 affects Rev-mediated post-transcriptional processes by using a CMV-promoter driven Gag-Pol-RRE expression plasmid as a reporter. HeLa cells were transfected with wild type and mutant Matrin 3 together with pCMV Gag-Pol RRE, as indicated; and 24 hours later, cells were harvested and cell lysates were analyzed by Western blotting. Figure 1B (lanes 1 and 2) shows that Matrin 3 did not alter the expression of Gag in the absence of Rev; however, in the presence of Rev, Matrin 3 increased Gag expression by approximately 10 fold (Figure 1B, lanes 3 and 4). These results support a role for Matrin 3 in Rev-dependent expression of RRE-containing HIV-1 transcripts.
The CTE is a cis-motif found in RNAs from simple type D retroviruses . It recruits cellular RNA-binding proteins that act to export unspliced or partially spliced viral mRNAs from the nucleus into the cytoplasm [39, 41]. Artificial placement of the CTE into HIV-1 Gag RNA facilitates its cytoplasmic export and expression, independent of Rev/RRE function . Indeed, CTE and Rev/RRE describe two separate pathways such that the inhibition of either pathway does not affect the export of RNA through the other pathway [34, 35]. We next assayed a Gag expression vector in which the RRE was replaced with a CTE. Unlike the results from Gal-Pol-RRE (Figure 1b), we found that the over expression of Matrin 3 had no effect on Gag-Pol-CTE expression (Figure 1C, lanes 5 and 6).
Matrin 3 interacts with Rev
Matrin 3 RNA recognition motifs (RRM) 3 are required for activity on Rev/RRE
Matrin 3 increases the stability and nuclear export of HIV-1 RRE-containing transcripts
We next investigated the consequence of increased Matrin 3 expression on cytoplasmic distribution of unspliced versus spliced viral RNAs. We co-transfected HeLa cells with pNL4-3 and Matrin 3, and fractionated cellular RNAs into total, cytoplasmic, or nuclear constituents. We isolated the RNAs from these fractions and analyzed them by qRT-PCR for the levels of unspliced and spliced RNAs using primers specific for the 9 kb or the 1.8 kb viral RNA. We used GAPDH as a normalization control for our fractionation (GAPDH; Figure 5B). Consistent with the Northern blot results, there was a 3 fold increase in expression of unspliced viral RNA in the cells (total 9 kb; Figure 5B), but interestingly the amount of 9 kb viral RNA distributed into the cytoplasm of pCMV-HA-Matrin 3 expressing cells was 10 fold higher than that found in pCMV-HA expressing cells (cytoplasmic 9 kb; Figure 5B; also see Additional file 3, Figure S3). By contrast, the distribution and expression of spliced RNA remained unchanged in the presence of increased Matrin 3 expression (1.8 kb; Figure 5B). These results are consistent with the interpretation that Matrin 3 can selectively stabilize and increase the nuclear to cytoplasmic distribution of unspliced 9 kb vs. spliced 1.8 kb HIV-1 RNAs.
Here, we have shown that nuclear matrix protein Matrin 3 influences the expression of HIV-1 RRE-containing mRNAs. Matrin 3 acts post-transcriptionally via Rev/RRE to increase the expression of HIV-1 Rev/RRE dependent unspliced or partially spliced transcripts. This activity requires Matrin 3 to bind Rev-dependent RRE-containing RNA and appears to lead to the stabilization and nuclear to cytoplasmic export of RRE-containing HIV-1 transcripts.
Previously it was shown that Matrin 3 exists in cells complexed with PSF (PTBP associated splicing factor) and nrbp54 [53, 65–67]. Others have found that PSF binds to instability elements (INS) contained within the HIV-1 transcripts and suppresses the expression of these RNAs . The INS elements are primarily present in the RRE-containing unspliced and partially spliced viral transcripts [31, 64, 68–72]. It is possible that some of the effects that we have observed from Matrin 3 may be due to its interaction with PSF and p54nrb. That Matrin 3 might counter the reported PSF-suppression of RNA expression has not been explored here, but it remains important to establish and clarify this mechanistic interaction in the future.
Our results are compatible with a model in which Matrin 3 binds to RRE containing transcripts and stabilizes them in the presence of Rev, which then directs these viral transcripts for export out of the nucleus. This interpretation is supported by our observation that Rev - Matrin 3 interaction is RRE-RNA dependent, and Matrin 3 activity requires the presence of Rev and RRE-containing RNA. Further experiments are needed to answer the mechanistic details of how Matrin 3 and Rev cooperate in their interactions with RRE-containing RNA. One intriguing finding is that Matrin 3 has been identified as a constituent of the nuclear pore proteomes ; this localization would be compatible with Matrin 3 being a part of an RNP-complex that exits the nucleus into the cytoplasm through the nuclear pore. Also of interest, Bushman et al.  recently performed a meta-analysis of published genome-wide siRNA screening of cellular factors important for HIV-1 replication. They used a graph theory clustering algorithm (MCODE) to assemble a HIV-1 host interactome in which nuclear matrix structure (Matrin 3) was identified as an interactor with the molecular chaperone cluster identified by siRNA-screening as involved in the assembly of viral proteins. Our evidence here for a role of Matrin 3 in HIV-1 post-transcriptional RNA expression is consistent with the above analysis. In conclusion, the implication of Matrin 3 as an additional Rev co-factor adds further complexity to the understanding of post-transcriptional regulation of unspliced/partially spliced HIV-1 RNA. Although it remains to be established, Matrin 3 may be a cellular factor that counters the nuclear retention through INS elements of HIV-1 unspliced/partially spliced RNAs.
Materials and methods
Full-length Matrin 3 clone was purchased from Open Biosystems and cloned into pCMV-HA vector (Clontech) by PCR. HIV-1 LTR luciferase plasmid, pCMV-NL-GagPol-RRE and pCMV-NL-GagPol-CTE were from E. Freed and D. Rekosh. Plasmids p37 and p37RRE were kindly provided by B. Felber  and cloned into pcDNA3.
Cell Culture, Transfection, and Reporter Assays
Cell propagation, transfection, qRT-PCR and reporter assays were as described previously [28, 29]. All transfections were repeated three or more times and were normalized to β-galactosidase activity expressed from a co-transfected pCMV-β (Clontech).
Mouse monoclonal anti-HA (Sigma Chemical); mouse monoclonal Matrin 3, (Abcam) and rabbit anti-GFP and anti-HA (Cell Sciences) are commercially available.
Western Blotting, and Immunoprecipitation
Western blotting and immunoprecipitation were performed as described previously [28, 29]. Briefly, the cells were washed twice with PBS and lysed with sample buffer [100 mMTris (pH6.8), 4%SDS, 20% glycerol, 5% β-mercaptoethanol, and 0.05% bromophenol blue]. Cell lysates were boiled for 10 minutes, and loaded onto a SDS/PAGE gel and electrophoresed. The gel was electroblotted onto Immobilon-P membranes (Millipore) and probed with the primary antibodies, followed by incubation with anti-rabbit, anti-mouse, or anti-human alkaline phosphatase-conjugated secondary antibody and detected using a chemiluminescence substrate (Applied Biosystems).
RNA isolation, Northern blotting and qRT-PCR
Total RNA from cells was extracted with Tri-Reagent (Sigma-Aldrich). Nuclear and cytoplasmic RNAs were isolated by cell fractionation (Paris Kit; Applied Biosystems), and RNA was isolated with Tri-Reagent. Northern blots were performed as described previously . Extracted RNA was analyzed by qRT-PCR using the iScript One-Step RT-PCR Kit with SYBR Green (Bio-Rad) according to manufacturer's instructions. Samples were reverse-transcribed at 50°C for 30 minutes, and amplification was performed after an initial step at 95°C for 10 minutes, followed by 20-40 cycles at 95°C for 30 s, 55°C for 30 s, and 72°C for 60 s. The primers and their sequences used in the analyses have been previously described . Primers for unspliced transcripts were Primer A 5′-GTCTCTCTGGTTAGACCAG-3′, Primer C 5′-CTAGTCAAAATTTTTGGCGTACTC-3′ and primer A and sj4.7A 5′- TTGGGAGGTGGGTTGCTTTGATAGAG-3 for spliced 2 Kb transcript. For GAPDH forward 5′ CTCTGCTCCTCCTGTTCGAC 3′ and GAPDH reverse 5′ TTAAAAGCAGCCCTGGTGAC 3′ primers were used.
Co-immunoprecipitation assay has been described previously [28, 29]. Cell lysates were prepared in RIPA buffer [Tris-buffered saline (pH 8.0) containing 1% Triton X-100 or Nonidet P-40, 1 mg of BSA/mL, and 1 mM EDTA] containing (phenylmethylsulfonyl fluoride and aprotinin 10 μg/mL), 0.5% sodium deoxycholate, and 0.1% SDS. Cell lysates were prepared and incubated at 4°C overnight with the indicated antibodies and immune complexes were pulled down using protein G-agarose beads and analyzed by Western blotting.
Work in KTJ's laboratory was supported in part by Intramural funds from NIAID, and by the Intramural AIDS Targeted Antiviral Program (IATAP) from the office of the Director, NIH. We thank members of KTJ's laboratory for reading and commenting on the manuscript, and Barbara Felber for sharing several critical reagents. We are grateful to Anna Kula and Alessandro Marcello for sharing data in their paper prior to publication .
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