PMID- 24600008
OWN - NLM
STAT- MEDLINE
DCOM- 20140615
LR  - 20211203
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 88
IP  - 10
DP  - 2014 May
TI  - Functional evidence for the involvement of microtubules and dynein motor 
      complexes in TRIM5alpha-mediated restriction of retroviruses.
PG  - 5661-76
LID - 10.1128/JVI.03717-13 [doi]
AB  - The tripartite motif (TRIM) family of proteins includes the TRIM5alpha antiretroviral 
      restriction factor. TRIM5alpha from many Old World and some New World monkeys can 
      restrict the human immunodeficiency virus type 1 (HIV-1), while human TRIM5alpha 
      restricts N-tropic murine leukemia virus (N-MLV). TRIM5alpha forms highly dynamic 
      cytoplasmic bodies (CBs) that associate with and translocate on microtubules. 
      However, the functional involvement of microtubules or other 
      cytoskeleton-associated factors in the viral restriction process had not been 
      shown. Here, we demonstrate the dependency of TRIM5alpha-mediated restriction on 
      microtubule-mediated transport. Pharmacological disruption of the microtubule 
      network using nocodazole or disabling it using paclitaxel (originally named 
      taxol) decreased the restriction of N-MLV and HIV-1 by human or simian alleles of 
      TRIM5alpha, respectively. In addition, pharmacological inhibition of dynein motor 
      complexes using erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and small interfering 
      RNA-mediated depletion of the dynein heavy chain (DHC) similarly decreased 
      TRIM5alpha-mediated restriction. The loss in restriction resulting from either the 
      disassembly of microtubules or the disruption of dynein motor activity was seen 
      for both endogenous and overexpressed TRIM5alpha and was not due to differences in 
      protein stability or cell viability. Both nocodazole treatment and DHC depletion 
      interfered with the dynamics of TRIM5alpha CBs, increasing their size and altering 
      their intracellular localization. In addition, nocodazole, paclitaxel, and DHC 
      depletion were all found to increase the stability of HIV-1 cores in infected 
      cells, providing an alternative explanation for the decreased restriction. In 
      conclusion, association with microtubules and the translocation activity of 
      dynein motor complexes are required to achieve efficient restriction by TRIM5alpha. 
      IMPORTANCE: The primate innate cellular defenses against infection by 
      retroviruses include a protein named TRIM5alpha, belonging to the family of 
      restriction factors. TRIM5alpha is present in the cytoplasm, where it can intercept 
      incoming retroviruses shortly after their entry. How TRIM5alpha manages to be present 
      at the appropriate subcytoplasmic location to interact with its target is 
      unknown. We hypothesized that TRIM5alpha, either as a soluble protein or a 
      high-molecular-weight complex (the cytoplasmic body), is transported within the 
      cytoplasm by a molecular motor called the dynein complex, which is known to 
      interact with and move along microtubules. Our results show that destructuring 
      microtubules or crippling their function decreased the capacity of human or 
      simian TRIM5alpha to restrict their retroviral targets. Inhibiting dynein motor 
      activity, or reducing the expression of a key component of this complex, 
      similarly affected TRIM5alpha-mediated restriction. Thus, we have identified specific 
      cytoskeleton structures involved in innate antiretroviral defenses.
FAU - Pawlica, Paulina
AU  - Pawlica P
AD  - Laboratory of Retrovirology, Department of Medical Biology and BioMed Group, 
      Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada.
FAU - Le Sage, Valerie
AU  - Le Sage V
FAU - Poccardi, Nolwenn
AU  - Poccardi N
FAU - Tremblay, Michel J
AU  - Tremblay MJ
FAU - Mouland, Andrew J
AU  - Mouland AJ
FAU - Berthoux, Lionel
AU  - Berthoux L
LA  - eng
GR  - MOP-102712/Canadian Institutes of Health Research/Canada
GR  - MOP-110960/Canadian Institutes of Health Research/Canada
GR  - MOP-56974/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140305
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antiviral Restriction Factors)
RN  - 0 (Carrier Proteins)
RN  - 0 (Proteins)
RN  - 0 (Tripartite Motif Proteins)
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 3.6.4.2 (Dyneins)
SB  - IM
MH  - Animals
MH  - Antiviral Restriction Factors
MH  - Biological Transport
MH  - Carrier Proteins/*metabolism
MH  - Cell Line
MH  - Dyneins/*metabolism
MH  - HIV-1/*immunology
MH  - Humans
MH  - Leukemia Virus, Murine/*immunology
MH  - Macaca mulatta
MH  - Microtubules/*metabolism
MH  - Proteins/metabolism
MH  - Tripartite Motif Proteins
MH  - Ubiquitin-Protein Ligases
PMC - PMC4019117
EDAT- 2014/03/07 06:00
MHDA- 2014/06/16 06:00
PMCR- 2014/11/01
CRDT- 2014/03/07 06:00
PHST- 2014/03/07 06:00 [entrez]
PHST- 2014/03/07 06:00 [pubmed]
PHST- 2014/06/16 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - JVI.03717-13 [pii]
AID - 03717-13 [pii]
AID - 10.1128/JVI.03717-13 [doi]
PST - ppublish
SO  - J Virol. 2014 May;88(10):5661-76. doi: 10.1128/JVI.03717-13. Epub 2014 Mar 5.