Chloroquine Triggers Epstein-Barr Virus Replication Through Phosphorylation of KAP1/TRIM28 in Burkitt Lymphoma Cells

PLoS Pathog. 2017 Mar 1;13(3):e1006249. doi: 10.1371/journal.ppat.1006249. eCollection 2017 Mar.

Abstract

Trials to reintroduce chloroquine into regions of Africa where P. falciparum has regained susceptibility to chloroquine are underway. However, there are long-standing concerns about whether chloroquine increases lytic-replication of Epstein-Barr virus (EBV), thereby contributing to the development of endemic Burkitt lymphoma. We report that chloroquine indeed drives EBV replication by linking the DNA repair machinery to chromatin remodeling-mediated transcriptional repression. Specifically, chloroquine utilizes ataxia telangiectasia mutated (ATM) to phosphorylate the universal transcriptional corepressor Krüppel-associated Box-associated protein 1/tripartite motif-containing protein 28 (KAP1/TRIM28) at serine 824 -a mechanism that typically facilitates repair of double-strand breaks in heterochromatin, to instead activate EBV. Notably, activation of ATM occurs in the absence of detectable DNA damage. These findings i) clarify chloroquine's effect on EBV replication, ii) should energize field investigations into the connection between chloroquine and endemic Burkitt lymphoma and iii) provide a unique context in which ATM modifies KAP1 to regulate persistence of a herpesvirus in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Burkitt Lymphoma / virology*
  • Cell Line, Tumor
  • Chloroquine / pharmacology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Herpesvirus 4, Human / drug effects*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Phosphorylation
  • Polymerase Chain Reaction
  • RNA, Small Interfering
  • Repressor Proteins / metabolism*
  • Transfection
  • Tripartite Motif-Containing Protein 28
  • Virus Activation / physiology
  • Virus Replication / drug effects*

Substances

  • Antimalarials
  • RNA, Small Interfering
  • Repressor Proteins
  • Chloroquine
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28
  • Ataxia Telangiectasia Mutated Proteins