DRAM Triggers Lysosomal Membrane Permeabilization and Cell Death in CD4+ T Cells Infected with HIV

PLoS Pathogens

Mireille Laforge¹  Houda Haloui¹  Anna Senik¹  Vasco Rodrigues¹  Sophie Limou²  Jerome Estaquier²  Francis Harper³  Nicoletta Casartelli⁴  Ricardo Silvestre⁵  Jean-Francois Zagury⁵ 

[1] CNRS FRE 3235, Université Paris Descartes, Paris, France;Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France;FRE 2937-Génétique Moléculaire et Intégration des Fonctions Cellulaires, Villejuif, France;Institut Pasteur, Unité Virus et Immunité, Paris, France;Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

关键词: T cells;    Autophagic cell death;    Small interfering RNAs;    Lysosomes;    HIV-1;    HIV infections;    Cell staining;    Apoptosis;   

DOI  :  10.1371/journal.ppat.1003328

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Productive HIV infection of CD4+ T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells.

【 授权许可】

CC BY