A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5? important for NF-?B/AP-1 signaling and HIV-1 restriction.

ABSTRACT: TRIM5? from the rhesus macaque (TRIM5?Rh) is a restriction factor that shows strong activity against HIV-1. TRIM5?Rh binds specifically to HIV-1 capsid (CA) through its B30.2/PRYSPRY domain shortly after entry of the virus into the cytoplasm. Recently, three putative SUMO interacting motifs (SIMs) have been identified in the PRYSPRY domain of human and macaque TRIM5?. However, structural modeling of this domain suggested that two of them were buried in the hydrophobic core of the protein, implying that interaction with SUMO was implausible, while the third one was not relevant to restriction. In light of these results, we re-analyzed the TRIM5?Rh PRYSPRY sequence and identified an additional putative SIM ((435)VIIC(438)) which we named SIM4. This motif is exposed at the surface of the PRYSPRY domain, allowing potential interactions with SUMO or SUMOylated proteins. Introducing a double mutation in SIM4 (V435K, I436K) did not alter stability, unlike mutations in SIM1. SIM4-mutated TRIM5?Rh failed to bind HIV-1CA and lost the ability to restrict this virus. Accordingly, SIM4 undergoes significant variation among primates and substituting this motif with naturally occurring SIM4 variants affected HIV-1 restriction by TRIM5?Rh, suggesting a direct role in capsid recognition. Interestingly, SIM4-mutated TRIM5?Rh also failed to activate NF-?B and AP-1-mediated transcription. Although there is no direct evidence that SIM4 is involved in direct interaction with SUMO or a SUMOylated protein, mutating this motif strongly reduced co-localization of TRIM5?Rh with SUMO-1 and with PML, a SUMOylated nuclear protein. In conclusion, this new putative SIM is crucial for both direct interaction with incoming capsids and for NF-?B/AP-1 signaling. We speculate that the latter function is mediated by interactions of SIM4 with a SUMOylated protein involved in the NF-?B/AP-1 signaling pathways.

SUBMITTER: Nepveu-Traversy ME 

PROVIDER: S-EPMC4945854 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature