Human tripartite motif 5alpha domains responsible for retrovirus restriction activity and specificity.
The tripartite motif 5alpha protein (TRIM5alpha) is one of several factors expressed by mammalian cells that inhibit retrovirus replication. Human TRIM5alpha (huTRIM5alpha) inhibits infection by N-tropic murine leukemia virus (N-MLV) but is inactive against human immunodeficiency virus type 1 (HIV-1). However, we show that replacement of a small segment in the carboxy-terminal B30.2/SPRY domain of huTRIM5alpha with its rhesus macaque counterpart (rhTRIM5alpha) endows it with the ability to potently inhibit HIV-1 infection. The B30.2/SPRY domain and an additional domain in huTRIM5alpha, comprising the amino-terminal RING and B-box components of the TRIM motif, are required for N-MLV restriction activity, while the intervening coiled-coil domain is necessary and sufficient for huTRIM5alpha multimerization. Truncated huTRIM5alpha proteins that lack either or both the N-terminal RING/B-Box or the C-terminal B30.2/SPRY domain form heteromultimers with full-length huTRIM5alpha and are dominant inhibitors of its N-MLV restricting activity, suggesting that homomultimerization of intact huTRIM5alpha monomers is necessary for N-MLV restriction. However, localization in large cytoplasmic bodies is not required for inhibition of N-MLV by huTRIM5alpha or for inhibition of HIV-1 by chimeric or rhTRIM5alpha.
Aaron Diamond AIDS Research Center, 455 First Ave., New York, NY 10021, USA.
David
D
Perez-Caballero
Theodora
T
Hatziioannou
Annie
A
Yang
Simone
S
Cowan
Paul D
PD
Bieniasz
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000502:physiology*; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000737:chemistry* / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009052:Leukemia Virus, Murine / Q000502:physiology; D008969:Molecular Sequence Data; D012192:Retroviridae Infections / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D000998:Antiviral Agents; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases