HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway

Ankit Shah,Naveen K Vaidya,Anil Kumar,Hari K Bhat

doi:10.1038/srep18929

Abstract

The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1α pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1α pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1α also increased XBP-1 splicing. The functional consequence of gp120-mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1α, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS.

Highlights

Endoplasmic reticulum (ER) performs several cellular processes such as synthesis and folding of protein, calcium storage and lipid biosynthesis[9,10,11]
Our findings in current report for the first time demonstrate that HIV-1 gp120-mediated astrocytic apoptosis involves ER stress
Increase in ER stress, as indicated by increase in the levels of BiP and C/EBP homologous protein (CHOP), activated caspase cascade in this process leading to cell death

Summary

Introduction

Endoplasmic reticulum (ER) performs several cellular processes such as synthesis and folding of protein, calcium storage and lipid biosynthesis[9,10,11]. While several chaperone proteins, oxidizing and glycosylating enzymes and ATP are required to execute these processes, oxidative stress, calcium dysregulation, and lipid overload in the ER lumen[12] lead to increased unfolded or mis-folded proteins. The accumulation of these unfolded proteins induce unfolded protein response (UPR) and ER-associated degradation (ERAD)[13]. The apoptotic cell death is well documented to play an important role in the CNS toxicity of a variety of neurological disorders It is not known whether ER stress-mediated apoptosis plays any role in the CNS toxicity in HIV infected patients. We determined the possible role of IRE1 signaling cascade in HIV-1 gp120-mediated apoptosis

Methods

Results

Conclusion