HIV Nef Enhances Tat-Mediated Viral Transcription through a hnRNP-K-Nucleated Signaling Complex

Wolf, Dietlinde; Witte, Vanessa; Clark, Pat; Blume, Katja; Lichtenheld, Mathias G.; Baur, Andreas S.

doi:10.1016/j.chom.2008.08.013

Cited by 43 publications

(53 citation statements)

References 41 publications

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“…hnRNP K exists in complexes with ERK1/2 and regulates their activities (40,82). We show that in response to serum treatment, hnRNP K recruitment along the EGR-1 gene is linked to Pol II transcription (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Mikula

Bomsztyk

2011

Journal of Biological Chemistry

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Components of the ERK cascade are recruited to genes, but it remains unknown how they are regulated at these sites. The RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) K interacts with kinases and is found along genes including the mitogen-inducible early response gene EGR-1. Here, we used chromatin immunoprecipitations to study co-recruitment of hnRNP K and ERK cascade activity along the EGR-1 gene. These measurements revealed that the spatiotemporal binding patterns of ERK cascade transducers (GRB2, SOS, B-Raf, MEK, and ERK) at the EGR-1 locus resemble both hnRNP K and RNA polymerase II (Pol II). Inhibition of EGR-1 transcription with either serum-responsive factor knockdown or 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole altered recruitment of all of the above ERK cascade components along this locus that mirrored the changes in Pol II and hnRNP K profiles. siRNA knockdown of hnRNP K decreased the levels of active MEK and ERK at the EGR-1, changes associated with decreased levels of elongating pre-mRNA and less efficient splicing. The hnRNP K dependence and pattern of ERK cascade activation at the c-MYC locus were different from at EGR-1. Ribonucleoprotein immunoprecipitations revealed that hnRNP K was associated with the EGR-1 but not c-MYC mRNAs. These data suggest a model where Pol II transcription-driven recruitment of hnRNP K along the EGR-1 locus compartmentalizes activation of the ERK cascade at these genes, events that regulate synthesis of mature mRNA.

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Section: Discussionmentioning

confidence: 99%

“…hnRNP K acts as a docking platform at sites of RNA-directed processes (22,31,82). hnRNP K exists in complexes with ERK1/2 and regulates their activities (40,82).…”

Section: Discussionmentioning

confidence: 99%

Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Mikula

Bomsztyk

2011

Journal of Biological Chemistry

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“…plex (22). In another study, Hsp40 was shown to interact and co-localize with Nef in the nucleus and thereby augment LTRdriven gene expression (23).…”

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confidence: 99%

“…The complex between CycK and CDK9 was also shown to function as a CTD kinase in vitro (17). Although Nef was earlier reported as a negative factor for viral replication (32), recent evidence has convincingly demonstrated Nef as an enhancer of viral replication (16,22,(33)(34)(35)(36). Nef performs most of its functions by interacting with cellular proteins.…”

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confidence: 99%

Cyclin K Inhibits HIV-1 Gene Expression and Replication by Interfering with Cyclin-dependent Kinase 9 (CDK9)-Cyclin T1 Interaction in Nef-dependent Manner

Khan

Mitra

2011

Journal of Biological Chemistry

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Human immunodeficiency virus type-1 (HIV-1) perpetuates its survival in the host by utilizing multiple strategies such as irreversible integration of its DNA into the host cell genome to establish the provirus (1), diversification of its genome to escape or tolerate adaptive immune responses (2), and use of the accessory genes (nef, vif, vpu, and vpr) to modulate host cell immune responses further (3-5). These viral accessory genes are frequently seen as dispensable in many in vitro cell culture systems but seem to be indispensable, in the context of natural infections in vivo. Among these accessory genes, pleiotropic functions of Nef have been studied extensively. It is a 27-30-kDa, N-terminally myristoylated protein having a well characterized CD4 down-regulatory activity (6). Nef does not possess any enzymatic activity, but it modulates diverse signaling pathways and the gene expression of host cell proteins (7,8). Furthermore, Nef influences the activation state of the host cell by bringing together different host cell proteins, protein kinases, and components of the endocytic machinery and making the cells permissible to the virus (9, 10). All these functions of Nef are manifested by a number of events such as activation of signaling molecules, modulation of apoptosis, activation of transcription factors, mitigation of transcriptional repressors, and an increase in the infectivity of virions (11). Although these functions of Nef have been well studied, controversy exists on its role in viral infectivity and replication as both negative (12, 13) and positive (14, 15) roles have been attributed in the literature. Although a number of reports show that Nef increases viral replication by activating T-cells, the molecular basis of Nef-induced viral gene expression and replication remains to be clearly elucidated. Nef was also shown to physically interact with Tat and augment viral gene expression (16), although availability of Tat is critical for the elongation step of long terminal repeat (LTR) 2 -driven transcription by RNA polymerase II. Several cellular factors have been identified for their roles in this process, including positive transcription elongation factor b (P-TEFb) complex. Different P-TEFb complexes isolated from mammalian cells contain a common catalytic subunit, cyclin-dependent kinase 9 (CDK9), and one of the regulatory cyclins, CycT1, CycT2a, CycT2b,. However, CycT1-containing P-TEFb complex is the key complex responsible for HIV-1 transcription elongation (19). Tat is expressed early in the replicative cycle of HIV and is essential for viral gene expression from the LTR promoter. It recognizes the 5Ј-bulge in the transactivation response stem loop RNA, which is located at the 5Ј-end of all viral transcripts. Tat binds to CycT1, and together they form the combinatorial surface that interacts with the transactivation response RNA with high affinity and specificity. The obligate partner of CycT1, CDK9, then hyperphosphorylates the C-terminal domain (CTD) of RNA polymerase II, resulting in incre...

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“…Second, Nef-mediated signaling can enhance Tat-mediated transcriptional activity via an extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK)-dependent pathway (225). Third, Nef promotes Tat-mediated transcription via the heterogeneous nuclear ribonucleoprotein K (hnRNP-K)-nucleated signaling complex (226). Note that hnRNP-K plays essential roles in transcriptional processes and molecular interactions (227).…”

Section: Tat-nef Interactionmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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HIV Nef Enhances Tat-Mediated Viral Transcription through a hnRNP-K-Nucleated Signaling Complex

Cited by 43 publications

References 41 publications

Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Direct Recruitment of ERK Cascade Components to Inducible Genes Is Regulated by Heterogeneous Nuclear Ribonucleoprotein (hnRNP) K

Cyclin K Inhibits HIV-1 Gene Expression and Replication by Interfering with Cyclin-dependent Kinase 9 (CDK9)-Cyclin T1 Interaction in Nef-dependent Manner

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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