Thriving under Stress: Selective Translation of HIV-1 Structural Protein mRNA during Vpr-Mediated Impairment of eIF4E Translation Activity

PLoS Pathogens

Kim Marsh¹  Alper Yilmaz²  Alan Cochrane³  Amit Sharma⁴  Kathleen Boris-Lawrie⁴ 

[1] Center for RNA Biology, Ohio State University, Columbus, Ohio, United States of America;Center for Retrovirus Research, Ohio State University, Columbus, Ohio, United States of America;Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America;Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio, United States of America

关键词: HIV-1;    Messenger RNA;    Protein translation;    Cell cycle;    cell division;    Protein synthesis;    Ribonucleoproteins;    Immunoblotting;    Actins;   

DOI  :  10.1371/journal.ppat.1002612

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Translation is a regulated process and is pivotal to proper cell growth and homeostasis. All retroviruses rely on the host translational machinery for viral protein synthesis and thus may be susceptible to its perturbation in response to stress, co-infection, and/or cell cycle arrest. HIV-1 infection arrests the cell cycle in the G2/M phase, potentially disrupting the regulation of host cell translation. In this study, we present evidence that HIV-1 infection downregulates translation in lymphocytes, attributable to the cell cycle arrest induced by the HIV-1 accessory protein Vpr. The molecular basis of the translation suppression is reduced accumulation of the active form of the translation initiation factor 4E (eIF4E). However, synthesis of viral structural proteins is sustained despite the general suppression of protein production. HIV-1 mRNA translation is sustained due to the distinct composition of the HIV-1 ribonucleoprotein complexes. RNA-coimmunoprecipitation assays determined that the HIV-1 unspliced and singly spliced transcripts are predominantly associated with nuclear cap binding protein 80 (CBP80) in contrast to completely-spliced viral and cellular mRNAs that are associated with eIF4E. The active translation of the nuclear cap binding complex (CBC)-bound viral mRNAs is demonstrated by ribosomal RNA profile analyses. Thus, our findings have uncovered that the maintenance of CBC association is a novel mechanism used by HIV-1 to bypass downregulation of eIF4E activity and sustain viral protein synthesis. We speculate that a subset of CBP80-bound cellular mRNAs contribute to recovery from significant cellular stress, including human retrovirus infection.

【 授权许可】

CC BY