Abstract
TRIM5α is an important host restriction factor that could potently block retrovirus infection. The SPRY domain of TRIM5α mediates post-entry restriction by recognition of and binding to the retroviral capsid. Human TRIM5α also functions as an innate immune sensor to activate AP-1 and NF-κB signaling, which subsequently restrict virus replication. Previous studies have shown that the AP-1 and NF-κB signaling activation relies on the RING motif of TRIM5α. In this study, we have demonstrated that the SPRY domain is essential for rhesus macaque TRIM5α to activate AP-1 but not NF-κB signaling. The AP-1 activation mainly depends on all of the β-sheet barrel on SPRY structure of TRIM5α. Furthermore, the SPRY-mediated auto-ubiquitination of TRIM5α is required for AP-1 activation. This study reports that rhesus macaque TRIM5α mainly undergoes Lys27-linked and Met1-linked auto-polyubiquitination. Finally, we found that the TRIM5α signaling function was positively correlated with its retroviral restriction activity. This study discovered an important role of the SPRY domain in immune signaling and antiviral activity and further expanded our knowledge of the antiviral mechanism of TRIM5α.
Highlights
TRIM5␣ is an important host restriction factor that could potently block retrovirus infection
We found that RhTRIM5␣ stimulated both nuclear factor-B (NF-B) and activator protein-1 (AP-1) transcriptional reporters with magnitudes similar to those of human TRIM5␣ (Fig. 1, A–C)
We found that RhTRIM5␣S453P and RhTRIM5␣VFVD degraded TAK1-binding protein 2 (TAB2) to the same level as RhTRIM5␣ (Fig. 4A), indicating that TAB2 degradation is independent of TRIM5␣-mediated AP-1 activation
Summary
TRIM proteins have a common structure named RBCC that features three major motifs: N-terminal RING, B-box, and coiled-coil domains. HuTRIM5␣ recruits E2 Ub-conjugating enzymes UBC13-UEV1A by the RING domain to generate free Lys63-linked polyubiquitination, resulting in TAK1 activation [9]. This study was planned to evaluate (i) whether and how the SPRY domain of RhTRIM5␣ contributes to innate immune signaling and (ii) whether this function is correlated to its antiviral activity. In this study, it was demonstrated for the first time that the SPRY domain of RhTRIM5␣ was vital for activating the AP-1 signal, but not NF-B. A significant finding was that RhTRIM5␣ mainly undergoes Lys27- and Met1-linked auto-ubiquitination
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