The cell death regulator GRIM-19 is involved in HIV-1 induced T-cell apoptosis

Abstract

One of the hallmarks of Human Immunodeficiency Virus-1 (HIV-1) infection is progressive depletion of the infected and bystander CD4+ T-cells by apoptosis. Different mitochondrial proteins have been implicated in this apoptotic process; however, the role of different subunits of mitochondrial oxidative phosphorylation (OXPHOS) complexes in apoptosis is not clearly understood. Some of the OXPHOS complex subunits seem to perform other functions in addition to their primary role in energy generating process. GRIM-19 (gene associated with retinoid-interferon-induced-mortality-19), a subunit of mitochondrial complex-I was previously implicated in Interferon-β and retionoic acid induced apoptosis in many tumor cells. In this study we report, using differential gene expression analysis, that GRIM-19 is up-regulated in HIV-1 infected apoptotic T-cells. A temporal up regulation of this subunit was observed in different HIV-1 infected T-cell lines and human PBMC and the extent of increase correlated to increasing apoptosis and virus production. Moreover, silencing GRIM-19 in HIV-1 infected cells reduced apoptosis, indicating its involvement in HIV-1 induced T-cell death.

Involvement of GRIM-19 in apoptosis induced in H5N1 virus-infected human macrophages

“…Up-regulation of GRIM-19 has been demonstrated to be correlated with the down-regulation of BCL-XL, which is one mechanism that viruses use to induce host cell apoptosis. 21 For example, in HIV-infected patients, both BCL-2 and BCL-XL were found to be markedly decreased in HIV-specific CD8 + T cells when compared with those in the healthy donors, thus resulting in an increased sensitivity to FASL-induced apoptosis. 26 Severe acute respiratory syndrome coronavirus infection could induce apoptosis by encoding 7 a protein to interact with BCL-XL and interfered with BCL-XL function.…”

“…HIV, the up-regulation of GRIM-19 could be observed when T-cells were exposed to the virus, leading to cell death of HIV-infected cells. 21 In contrast, some viruses avoid apoptosis by producing viral protein that can interact and inhibit GRIM-19 activity. For example, viral interferon regulatory factor-1 protein produced by human herpes virus-8 interacts with GRIM-19 and blocks the ability of GRIM-19 to induce apoptosis.…”

“…These results indicated a role of GRIM-19 in apoptotic induction via BID cleavage and AIF release. Because GRIM-19 expression has been shown to down-regulate the expression of anti-apoptotic protein BCL-XL during HIV infection, 21 the involvement of GRIM-19 in BCL-XL expression in H5N1 infection was also investigated. In this experiment, the GRIM-19-depleted hMDMs were infected with the virus for 8 h before the expression of BCL-XL was analyzed by RT-PCR.…”

Expression and functional characterization of a gene associated with retinoid-interferon-induced mortality 19 (GRIM-19) from orange-spotted grouper (Epinephelus coioides)

“…GRIM-19, a member of the GRIM family of genes, is a nuclear encoded subunit of complex I that has been implicated in apoptosis [21]. The protein participates in multiple functions including the innate immune response [8].…”

Inhibitor of Apoptosis (IAP)-like Protein Lacks a Baculovirus IAP Repeat (BIR) Domain and Attenuates Cell Death in Plant and Animal Systems

“…This functionally conserved process, known as programmed cell death (PCD) 5 or apoptosis, is genetically regulated and associated with distinct morphological and biochemical characteristics. Extensive study over the past decade has illuminated the biological and molecular mechanisms of the regulation of apoptosis in animal systems (2)(3)(4)(5)(6)(7). Apoptosis is triggered by the sequential activation of cysteine proteases known as caspases, which results in protein cleavage and the breakdown of DNA molecules.…”