Retromer Regulates HIV-1 Envelope Glycoprotein Trafficking and Incorporation into Virions
| Autor: | Alice C. L. Len, Luke A. Granger, Clare Jolly, Elisabetta Groppelli |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Retromer
QH301-705.5 Endosome viruses Immunology Vesicular Transport Proteins HIV Infections Endosomes Viral Structure Biology Virus Replication Microbiology Cell Line Viral Packaging VPS35 symbols.namesake RNA interference Virology Molecular Cell Biology Genetics Humans Biology (General) Molecular Biology Cell Membrane Virion env Gene Products Human Immunodeficiency Virus Biology and Life Sciences virus diseases Cell Biology RC581-607 Golgi apparatus Viral Replication 3. Good health Transport protein Cell biology Retromer complex Protein Transport HEK293 Cells Viral replication Cell Processes Viral Envelope HIV-1 symbols Parasitology Immunologic diseases. Allergy HeLa Cells Research Article |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 10, Iss 10, p e1004518 (2014) |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1004518 |
| Popis: | The envelope glycoprotein (Env) of the Human Immunodeficiency Virus Type-1 (HIV-1) is a critical determinant of viral infectivity, tropism and is the main target for humoral immunity; however, little is known about the cellular machinery that directs Env trafficking and its incorporation into nascent virions. Here we identify the mammalian retromer complex as a novel and important cellular factor regulating Env trafficking. Retromer mediates endosomal sorting and is most closely associated with endosome-to-Golgi transport. Consistent with this function, inactivating retromer using RNAi targeting the cargo selective trimer complex inhibited retrograde trafficking of endocytosed Env to the Golgi. Notably, in HIV-1 infected cells, inactivating retromer modulated plasma membrane expression of Env, along with Env incorporation into virions and particle infectivity. Mutagenesis studies coupled with coimmunoprecipitations revealed that retromer-mediated trafficking requires the Env cytoplasmic tail that we show binds directly to retromer components Vps35 and Vps26. Taken together these results provide novel insight into regulation of HIV-1 Env trafficking and infectious HIV-1 morphogenesis and show for the first time a role for retromer in the late-steps of viral replication and assembly of a virus. Author Summary Virus assembly necessitates the hijacking of the host cell machinery in order for new infectious viral particles to be constructed and disseminate. The envelope glycoprotein (Env) of HIV is a critical determinant of viral infectivity and is also a major target for antiviral immune responses. The long cytoplasmic tail of HIV Env plays an essential role in the assembly of infectious virions and limiting exposure of Env to the immune system, but the cellular machinery that transports HIV Env in virus-infected cells remain poorly understood. Here we have identified the mammalian retromer complex involved in endosomal sorting as a novel cellular factor regulating Env trafficking in virus-infected cells. We show that inactivating retromer alters Env localization, cell surface expression and incorporation into virions and that retromer binds directly to the Env cytoplasmic tail to perform these functions. This study defines an important pathway of Env transport and describes for the first time a role for this highly conserved cellular complex in assembly of a virus. |
| Databáze: | OpenAIRE |
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