Mechanism of Host Cell MAPK/ERK-2 Incorporation into Lentivirus Particles: Characterization of the Interaction between MAPK/ERK-2 and Proline-Rich-Domain Containing Capsid Region of Structural Protein Gag

Gupta, Pankaj; Singhal, Prabhat K.; Rajendrakumar, Palakurthy; Padwad, Yogendra; Tendulkar, Ashish V.; Kalyanaraman, Vaniambadi S.; Schmidt, Reinhold; Srinivasan, Abhay; Mahalingam, Sundarasamy

doi:10.1016/j.jmb.2011.03.022

Cited by 11 publications

(10 citation statements)

References 67 publications

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“…We have also predicted interaction of MAPK1 with the viral protein Gag_Pr55 with 71.43% confidence. In [29], the authors have shown that MAPK/ERK-2 interacts with the poly-proline motif present in the capsid region of Gag_Pr55. In [30], it is reported that HIV-1 Tat protein enhances RANKL (TNFSF)-mediated osteoclast differentiation.…”

Section: Resultsmentioning

confidence: 99%

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

2012

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Identification of potential viral-host protein interactions is a vital and useful approach towards development of new drugs targeting those interactions. In recent days, computational tools are being utilized for predicting viral-host interactions. Recently a database containing records of experimentally validated interactions between a set of HIV-1 proteins and a set of human proteins has been published. The problem of predicting new interactions based on this database is usually posed as a classification problem. However, posing the problem as a classification one suffers from the lack of biologically validated negative interactions. Therefore it will be beneficial to use the existing database for predicting new viral-host interactions without the need of negative samples. Motivated by this, in this article, the HIV-1–human protein interaction database has been analyzed using association rule mining. The main objective is to identify a set of association rules both among the HIV-1 proteins and among the human proteins, and use these rules for predicting new interactions. In this regard, a novel association rule mining technique based on biclustering has been proposed for discovering frequent closed itemsets followed by the association rules from the adjacency matrix of the HIV-1–human interaction network. Novel HIV-1–human interactions have been predicted based on the discovered association rules and tested for biological significance. For validation of the predicted new interactions, gene ontology-based and pathway-based studies have been performed. These studies show that the human proteins which are predicted to interact with a particular viral protein share many common biological activities. Moreover, literature survey has been used for validation purpose to identify some predicted interactions that are already validated experimentally but not present in the database. Comparison with other prediction methods is also discussed.

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Section: Resultsmentioning

confidence: 99%

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

2012

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“…Primary KSHV infection and reactivation trigger all three MAPK pathways (24,29,37,47,56,60,65,69,74,75,79), and the virus depends on these pathways for the initial establishment of infection and early gene expression (13,24,34,35,47,48,56,69). Though previous studies revealed that ERK2 associates with lentiviral particles (9,25,26,28,53), this is the first report of which we are aware that has characterized the association of any component of the MEK/ERK pathway with the virions of a herpesvirus. In the present study, we describe the incorporation of ERK2 in preference to ERK1 in the tegument of RRV particles and, for the first time, define distinct roles for these two isoforms in a herpesvirus infection.…”

mentioning

confidence: 78%

“…Mutation of the phosphosite in p6 gag leads to the accumulation of immature virions unable to separate from the host cell membrane (26). Further, a more recent paper by Gupta et al also showed that ERK2 is present in HIV-1 and simian immunodeficiency virus (SIV) particles and plays a role in phosphorylating viral proteins such as Vpr and Vpx that may be important for the replication of these viruses in nonreplicating primary cells (25).…”

Section: Discussionmentioning

confidence: 99%

Distinct Roles for Extracellular Signal-Regulated Kinase 1 (ERK1) and ERK2 in the Structure and Production of a Primate Gammaherpesvirus

Woodson

Kedes

2012

J Virol

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During their progression from intranuclear capsids to mature trilaminar virions, herpesviruses incorporate an extensive array of viral as well as a smaller subset of cellular proteins. Our laboratory previously reported that rhesus monkey rhadinovirus (RRV), a close homolog of the human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV), is comprised of at least 33 different virally encoded proteins. In the current study, we found that RRV infection activated the extracellular signal-regulated kinase (ERK) pathway and nascent virions preferentially incorporated the activated form of ERK2 (pERK2) into the tegument. This was evident even in the face of greatly diminished stores of intracellular ERK2, suggesting a clear bias toward the incorporation of pERK2 into the RRV particle. Similar to earlier findings with KSHV, activation of ERK was essential for the production of lytic viral proteins and virions. Knockdown of intracellular ERK, however, failed to inhibit virus production, likely due to maintenance of residual pools of intracellular pERK2. Paradoxically, selective knockdown of ERK1 enhanced virion production nearly 5-fold and viral titers more than 10-fold. These data are the first to implicate ERK1 as a negative regulator of lytic replication in a herpesvirus and the first to demonstrate the incorporation of an activated signaling molecule within a herpesvirus. Together, the results further our understanding of how herpesviruses interact with host cells during infection and demonstrate how this family of viruses can exploit cellular signal transduction pathways to modulate their own replication.

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“…It may be either argued for the conservation of a common mechanism of replication throughout viral evolution, or it may be considered as a proof for the non-specific association of proteins with distantly related viruses. In a number of cases, including for some kinases, evidence for the conservation of interaction motives in viral proteins together with functional studies of viruses unable to package these cellular factors proved that these components retain an evolutionarily conserved function [5-9]. …”

Section: Reviewmentioning

confidence: 99%

“…Although its function is not clearly elucidated, virus-associated ERK2 could assist early steps of HIV-1 replication either by supporting the establishment of a functional reverse transcription complex or by regulating nuclear import of the preintegration complexes. Very recent data have shown that ERK2 interacts with the poly-proline motif located near the cyclophilin binding loop at the N-terminus of HIV-1 CA domain of Gag [9]. This motif, conserved in distinct retroviruses, including in all subtypes of HIV-1, HIV-2, SIV, HTLV-I, HTLV-2 and other retroviruses, could account for the evolutionarily conserved incorporation of ERK2 in lentiviruses [5-8].…”

Section: Protein Kinases Packaged Into Hiv-1mentioning

confidence: 99%

Cellular kinases incorporated into HIV-1 particles: passive or active passengers?

2011

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Phosphorylation is one of the major mechanisms by which the activities of protein factors can be regulated. Such regulation impacts multiple key-functions of mammalian cells, including signal transduction, nucleo-cytoplasmic shuttling, macromolecular complexes assembly, DNA binding and regulation of enzymatic activities to name a few. To ensure their capacities to replicate and propagate efficiently in their hosts, viruses may rely on the phosphorylation of viral proteins to assist diverse steps of their life cycle. It has been known for several decades that particles from diverse virus families contain some protein kinase activity. While large DNA viruses generally encode for viral kinases, RNA viruses and more precisely retroviruses have acquired the capacity to hijack the signaling machinery of the host cell and to embark cellular kinases when budding. Such property was demonstrated for HIV-1 more than a decade ago. This review summarizes the knowledge acquired in the field of HIV-1-associated kinases and discusses their possible function in the retroviral life cycle.

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Mechanism of Host Cell MAPK/ERK-2 Incorporation into Lentivirus Particles: Characterization of the Interaction between MAPK/ERK-2 and Proline-Rich-Domain Containing Capsid Region of Structural Protein Gag

Cited by 11 publications

References 67 publications

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

Distinct Roles for Extracellular Signal-Regulated Kinase 1 (ERK1) and ERK2 in the Structure and Production of a Primate Gammaherpesvirus

Cellular kinases incorporated into HIV-1 particles: passive or active passengers?

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