PMID- 18497858
OWN - NLM
STAT- MEDLINE
DCOM- 20080805
LR  - 20211203
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 4
IP  - 5
DP  - 2008 May 23
TI  - Proteasomal degradation of TRIM5alpha during retrovirus restriction.
PG  - e1000074
LID - 10.1371/journal.ppat.1000074 [doi]
LID - e1000074
AB  - The host protein TRIM5alpha inhibits retroviral infection at an early 
      post-penetration stage by targeting the incoming viral capsid. While the detailed 
      mechanism of restriction remains unclear, recent studies have implicated the 
      activity of cellular proteasomes in the restriction of retroviral reverse 
      transcription imposed by TRIM5alpha. Here, we show that TRIM5alpha is rapidly 
      degraded upon encounter of a restriction-susceptible retroviral core. Inoculation 
      of TRIM5alpha-expressing human 293T cells with a saturating level of HIV-1 
      particles resulted in accelerated degradation of the HIV-1-restrictive rhesus 
      macaque TRIM5alpha protein but not the nonrestrictive human TRIM5alpha protein. 
      Exposure of cells to HIV-1 also destabilized the owl monkey restriction factor 
      TRIMCyp; this was prevented by addition of the inhibitor cyclosporin A and was 
      not observed with an HIV-1 virus containing a mutation in the capsid protein that 
      relieves restriction by TRIMCyp IVHIV. Likewise, human TRIM5alpha was rapidly 
      degraded upon encounter of the restriction-sensitive N-tropic murine leukemia 
      virus (N-MLV) but not the unrestricted B-MLV. Pretreatment of cells with 
      proteasome inhibitors prevented the HIV-1-induced loss of both rhesus macaque 
      TRIM5alpha and TRIMCyp proteins. We also detected degradation of endogenous 
      TRIM5alpha in rhesus macaque cells following HIV-1 infection. We conclude that 
      engagement of a restriction-sensitive retrovirus core results in TRIM5alpha 
      degradation by a proteasome-dependent mechanism.
FAU - Rold, Christopher James
AU  - Rold CJ
AD  - Department of Microbiology and Immunology, Vanderbilt University School of 
      Medicine, Nashville, Tennessee, United States of America.
FAU - Aiken, Christopher
AU  - Aiken C
LA  - eng
GR  - R56 AI050423/AI/NIAID NIH HHS/United States
GR  - T32GM008554/GM/NIGMS NIH HHS/United States
GR  - R01 AI050423/AI/NIAID NIH HHS/United States
GR  - T32 GM008554/GM/NIGMS NIH HHS/United States
GR  - T32AI060571/AI/NIAID NIH HHS/United States
GR  - R01 AI076121/AI/NIAID NIH HHS/United States
GR  - T32 AI060571/AI/NIAID NIH HHS/United States
GR  - AI050423/AI/NIAID NIH HHS/United States
GR  - AI76121/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080523
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Antiviral Restriction Factors)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tripartite Motif Proteins)
RN  - 0 (Viral Core Proteins)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 2.3.2.27 (TRIM5 protein, human)
RN  - EC 2.3.2.27 (TRIM5(alpha) protein, rhesus monkey)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Antiviral Restriction Factors
MH  - Aotidae
MH  - Carrier Proteins/*metabolism
MH  - Cell Line
MH  - Cyclosporine/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Silencing
MH  - HIV-1/physiology
MH  - *Host-Pathogen Interactions
MH  - Humans
MH  - Macaca mulatta
MH  - *Proteasome Endopeptidase Complex
MH  - Proteins/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
MH  - Retroviridae/*physiology
MH  - *Reverse Transcription
MH  - Transfection
MH  - Tripartite Motif Proteins
MH  - Ubiquitin-Protein Ligases
MH  - Viral Core Proteins/metabolism
PMC - PMC2374908
COIS- The authors have declared that no competing interests exist.
EDAT- 2008/05/24 09:00
MHDA- 2008/08/06 09:00
PMCR- 2008/05/23
CRDT- 2008/05/24 09:00
PHST- 2007/07/23 00:00 [received]
PHST- 2008/04/16 00:00 [accepted]
PHST- 2008/05/24 09:00 [pubmed]
PHST- 2008/08/06 09:00 [medline]
PHST- 2008/05/24 09:00 [entrez]
PHST- 2008/05/23 00:00 [pmc-release]
AID - 07-PLPA-RA-0467R3 [pii]
AID - 10.1371/journal.ppat.1000074 [doi]
PST - epublish
SO  - PLoS Pathog. 2008 May 23;4(5):e1000074. doi: 10.1371/journal.ppat.1000074.