Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

Abstract

The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

“…Following TAR binding, Tat is able to recruit the cellular apparatus that promotes chromatin‐remodelling and phosphorylation of RNA polymerase II. This enhances the processivity of the elongating polymerase and stimulates the assembly of new transcription complexes . Beyond its role on viral transcription, Tat has been proposed to modulate the expression of several other genes, to interact with a large number of host cell proteins, and to inhibit several cellular metabolic pathways .…”

“…stimulates the assembly of new transcription complexes. [4][5][6][7] Beyond its role on viral transcription, Tat has been proposed to modulate the expression of several other genes, to interact with a large number of host cell proteins, 8 and to inhibit several cellular metabolic pathways. 9,10 This modulatory activity of Tat has also been implicated in HIV-uninfected cells, where extracellular Tat can be internalized and directly stimulate cells through a bystander effect.…”

“…18,19 Of these, CHOP has been identified as one of the most important mediators of ER stress-induced apoptosis. 18 Although a growing body of evidence has demonstrated an intrinsic relationship between Tat trans-activating effects and increased apoptosis associated with AIDS, 5,6,9,20 this molecular network remains only partially understood. In fact, the hypothesis of Tat involvement in the pathogenesis of AIDS is reinforced by evidence that soluble, fulllength Tat is found at detectable levels in sera of HIV affected individuals.…”

HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

“…Therefore, we speculated that abnormal expression of BAG3 in astrocytes might be also caused by HIV-1 Tat. HIV-1 Tat is one of the most important HIV-encoded proteins, and as a trans-activator of transcription, plays a pivotal role in the viral transcription [10], and development of HAND [15,16]. In transgenic mouse, the expression of HIV-1 Tat in astrocytes causes learning and memory deficits [17], and is associated with thinning of the cerebral cortex [18] and synaptodendritic injury [19].…”

Recognition of Apoptotic Cells by Viruses and Cytolytic Lymphocytes: Target Selection in the Fog of War

“…This would prevent dead-end entry into doomed hosts, which are incapable of supporting productive infection. For example, HIV and SIV replicate primarily in a setting of increased uninfected CD4 + lymphocyte proliferation and turnover, marked by activation-induced cell death due to Fas and other contact-triggered suicide initiators, including uninfected cell contact with infected cells (13,30,51,57,60,64,87). Most leukocytes die within 12 h of initiating programmed cell death in vitro, and cell machinery required for viral integration, replication, assembly, and budding is compromised much sooner (23).…”