Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5.
TRIM5alpha and TRIMCyp are retroviral restriction factors that, like other members of the tripartite motif (TRIM) family, contain RING, B-box 2 and coiled-coil domains. We found that both proteins are rapidly turned over, with half-lives of 50-60 min. Polyubiquitylation and rapid degradation of TRIM5alpha depended upon intact RING and B-box 2 domains. A chimera consisting of monkey TRIM5alpha with a RING domain of human TRIM21 exhibited a half-life of 210 min, yet potently restricted human immunodeficiency virus; therefore, rapid turnover of TRIM5alpha is not required for its antiretroviral activity. TRIM5alpha forms cytoplasmic bodies that contain other polyubiquitylated proteins, heat shock proteins and dynein, and thus resemble aggresome precursors. Consistent with this interpretation, proteasomal inhibitors triggered the formation of TRIM5alpha(rh)-containing aggresomes in a microtubule-dependent manner. Thus, TRIM5alpha levels in the cell are maintained by continuous synthesis and rapid proteasome-mediated degradation, imbalances in which result in the formation of pre-aggresomal cytoplasmic bodies.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
Felipe
F
Diaz-Griffero
Xing
X
Li
Hassan
H
Javanbakht
Byeongwoon
B
Song
Sohanya
S
Welikala
Matthew
M
Stremlau
Joseph
J
Sodroski
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004398:Dyneins / Q000032:analysis; D015497:HIV-1 / Q000502:physiology; D006207:Half-Life; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D046911:Macromolecular Substances / Q000032:analysis; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D015739:Nocodazole / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D011506:Proteins; D000070584:Tripartite Motif Proteins; D025821:Polyubiquitin; C477346:TRIM5 protein, human; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D004398:Dyneins; D015739:Nocodazole