Inhibition of the Dead Box RNA Helicase 3 prevents HIV-1 Tat and cocaine-induced neurotoxicity by targeting microglia activation

Mapping Intimacies ◽

10.1101/591438 ◽

2019 ◽

Cited By ~ 1

Author(s):

Marina Aksenova ◽

Justin Sybrandt ◽

Biyun Cui ◽

Vitali Sikirzhytski ◽

Hao Ji ◽

...

Keyword(s):

Microglial Activation ◽

Drugs Of Abuse ◽

Viral Proteins ◽

Rna Helicase ◽

Literature Mining ◽

Tat Protein ◽

Mining System ◽

Dead Box ◽

Neuronal Toxicity ◽

Hiv 1

AbstractHIV-1 Associated Neurocognitive Disorder (HAND) is commonly seen in HIV-infected patients. Viral proteins including Tat cause neuronal toxicity and is worsened by drugs of abuse. To uncover potential targets for anti-HAND therapy, we employed a literature mining system, MOLIERE. Here, we validated Dead Box RNA Helicase 3 (DDX3) as a target to treat HAND via a selective DDX3 inhibitor, RK-33. The combined neurotoxicity of Tat protein and cocaine was blocked by RK-33 in rat and mouse cortical cultures. Transcriptome analysis showed that Tat-activated transcripts include makers and regulators of microglial activation, and RK-33 blocked Tat-induced activation of these mRNAs. Elevated production of proinflammatory cytokines was also inhibited by RK-33. These findings show that DDX3 contributes to microglial activation triggered by Tat and cocaine, and DDX3 inhibition shows promise as a therapy for HAND. Moreover, DDX3 may contribute to the pathology of other neurodegenerative diseases with pathological activation of microglia.

Involvement of Epigenetic Promoter DNA Methylation of miR-124 in the Pathogenesis of HIV-1-Associated Neurocognitive Disorders

Epigenetics Insights ◽

10.1177/2516865718806904 ◽

2018 ◽

Vol 11 ◽

pp. 251686571880690 ◽

Cited By ~ 2

Author(s):

Shilpa Buch ◽

Palsamy Periyasamy ◽

Minglei Guo

Keyword(s):

Dna Methylation ◽

Microglial Activation ◽

Viral Proteins ◽

Neurocognitive Disorders ◽

Microglial Cells ◽

Adjunctive Treatment ◽

Viral Reservoirs ◽

Stat3 Signaling ◽

Promoter Dna ◽

Hiv 1

Despite the efficacy of combination antiretroviral therapy (cART) in controlling viremia, the central nervous system (CNS) continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Transactivator of transcription (HIV-1 Tat) protein. Based on the premise that cART does not impact levels of HIV-1 Tat, and since the CNS is inaccessible to the cART regimens, HIV-1-Tat-mediated neuroinflammation has been implicated as an underlying mediator of HIV-1-associated neurocognitive disorders (HAND). The mechanism(s) underlying the pathogenesis of HAND, however, remain less understood. Understanding the epigenetic/molecular mechanism(s) by which viral proteins such as HIV-1 Tat activate microglia is thus of paramount importance. The study published by Periyasamy et al provides new mechanistic insights into the role of HIV-1-Tat-mediated DNA methylation of miR-124 promoter in regulating microglial activation via the MECP2-STAT3 signaling axis. Furthermore, the authors have also reported that exposure of mouse primary microglial cells to HIV-1 Tat notably increased DNA methylation of primary miR-124-1 and primary miR-124-2 promoters (with no change in primary miR-124-3), resulting in turn to downregulated expression of both primary miR-124-1 and primary miR-124-2 as well as mature miR-124 in mouse primary microglial cells. The authors also examined the involvement of MECP2-STAT3 signaling in HIV-1-Tat-mediated microglial activation. Based on these novel findings, it is evident that dysregulation of miR-124 is involved in the pathogenesis of HAND and that restoration of miR-124 could serve as an adjunctive treatment for dampening neuroinflammation associated with HAND.

Altered outward-rectifying K+ current reveals microglial activation induced by HIV-1 Tat protein

Glia ◽

10.1002/1098-1136(200103)33:3<181::aid-glia1017>3.0.co;2-q ◽

2001 ◽

Vol 33 (3) ◽

pp. 181-190 ◽

Cited By ~ 20

Author(s):

Sergio Visentin ◽

Massimiliano Renzi ◽

Giulio Levi

Keyword(s):

Microglial Activation ◽

Tat Protein ◽

K Current ◽

Hiv 1

Requirement of DDX3 DEAD Box RNA Helicase for HIV-1 Rev-RRE Export Function

Cell ◽

10.1016/j.cell.2004.09.029 ◽

2004 ◽

Vol 119 (3) ◽

pp. 381-392 ◽

Cited By ~ 355

Author(s):

Venkat S.R.K. Yedavalli ◽

Christine Neuveut ◽

Ya-hui Chi ◽

Lawrence Kleiman ◽

Kuan-Teh Jeang

Keyword(s):

Rna Helicase ◽

Dead Box ◽

Hiv 1

The proline–arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis

Cell Death and Disease ◽

10.1038/s41419-018-1028-5 ◽

2018 ◽

Vol 9 (10) ◽

Cited By ~ 12

Author(s):

Hiroaki Suzuki ◽

Yoshio Shibagaki ◽

Seisuke Hattori ◽

Masaaki Matsuoka

Keyword(s):

Ribosome Biogenesis ◽

Rna Helicase ◽

Repeat Protein ◽

Dead Box ◽

Neuronal Toxicity ◽

The Dead

A HIV-1 Tat mutant protein disrupts HIV-1 Rev function by targeting the DEAD-box RNA helicase DDX1

Retrovirology ◽

10.1186/s12977-014-0121-9 ◽

2014 ◽

Vol 11 (1) ◽

Cited By ~ 20

Author(s):

Min-Hsuan Lin ◽

Haran Sivakumaran ◽

Alun Jones ◽

Dongsheng Li ◽

Callista Harper ◽

...

Keyword(s):

Rna Helicase ◽

Mutant Protein ◽

Dead Box ◽

The Dead ◽

Hiv 1

Structure of the SPRY domain of the human RNA helicase DDX1, a putative interaction platform within a DEAD-box protein

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x15013709 ◽

2015 ◽

Vol 71 (9) ◽

pp. 1176-1188 ◽

Cited By ~ 4

Author(s):

Julian N. Kellner ◽

Anton Meinhart

Keyword(s):

Protein Interaction ◽

Structural Information ◽

Tumour Progression ◽

Domain Architecture ◽

Rna Helicase ◽

Spry Domain ◽

Protein Protein Interaction ◽

Dead Box ◽

Loop Regions ◽

Hiv 1

The human RNA helicase DDX1 in the DEAD-box family plays an important role in RNA processing and has been associated with HIV-1 replication and tumour progression. Whereas previously described DEAD-box proteins have a structurally conserved core, DDX1 shows a unique structural feature: a large SPRY-domain insertion in its RecA-like consensus fold. SPRY domains are known to function as protein–protein interaction platforms. Here, the crystal structure of the SPRY domain of human DDX1 (hDSPRY) is reported at 2.0 Å resolution. The structure reveals two layers of concave, antiparallel β-sheets that stack onto each other and a third β-sheet beneath the β-sandwich. A comparison with SPRY-domain structures from other eukaryotic proteins showed that the general β-sandwich fold is conserved; however, differences were detected in the loop regions, which were identified in other SPRY domains to be essential for interaction with cognate partners. In contrast, in hDSPRY these loop regions are not strictly conserved across species. Interestingly, though, a conserved patch of positive surface charge is found that may replace the connecting loops as a protein–protein interaction surface. The data presented here comprise the first structural information on DDX1 and provide insights into the unique domain architecture of this DEAD-box protein. By providing the structure of a putative interaction domain of DDX1, this work will serve as a basis for further studies of the interaction network within the hetero-oligomeric complexes of DDX1 and of its recruitment to the HIV-1 Rev protein as a viral replication factor.