DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV

Mireille Laforge; Sophie Limou; Francis Harper; Nicoletta Casartelli; Vasco Rodrigues; Ricardo Silvestre; Houda Haloui; Jean-Francois Zagury; Anna Senik; Jerome Estaquier

doi:10.1371/journal.ppat.1003328

DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV

PLoS Pathog. 2013;9(5):e1003328. doi: 10.1371/journal.ppat.1003328. Epub 2013 May 2.

Authors

Mireille Laforge¹, Sophie Limou, Francis Harper, Nicoletta Casartelli, Vasco Rodrigues, Ricardo Silvestre, Houda Haloui, Jean-Francois Zagury, Anna Senik, Jerome Estaquier

Affiliation

¹ CNRS FRE 3235, Université Paris Descartes, Paris, France.

Abstract

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.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Autophagy*
Autophagy-Related Protein 5
CD4-Positive T-Lymphocytes* / metabolism
CD4-Positive T-Lymphocytes* / virology
Cytochromes c / genetics
Cytochromes c / metabolism
Female
Gene Expression Regulation
HIV / physiology*
HIV Infections / genetics
HIV Infections / metabolism*
Host-Pathogen Interactions / physiology*
Humans
Intracellular Membranes / metabolism*
Lysosomes / genetics
Lysosomes / metabolism*
Lysosomes / virology
Male
Membrane Proteins / biosynthesis*
Membrane Proteins / genetics
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Permeability
Tumor Suppressor Protein p53 / biosynthesis

Substances

ATG5 protein, human
Autophagy-Related Protein 5
DRAM1 protein, human
Membrane Proteins
Microtubule-Associated Proteins
TP53 protein, human
Tumor Suppressor Protein p53
Cytochromes c

Grants and funding

ML was supported by a fellowship from ANRS. RS was supported by Programa Ciência – financed by Programa OperacionalPotencial Humano POPH – QREN – Tipologia 4.2 – Promocão do Emprego Científico, co-funded by Fundo Social Europeu and National funding from Ministry of Science, Technology and Higher Education (MCTES). “Fondation pour la Recherche Médicale,” to JE and from CNRS and ARC to FH. VR is supported by fellowship from FCT code SFRH/BD/64064/2009. JE thanks the Canada Research Chair program for financial assistance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.