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Details on Person The Kaposi’s sarcoma-associated herpesvirus (KSHV) tegument ...
| Class:Id | Summation:9989204 |
|---|---|
| _displayName | The Kaposi’s sarcoma-associated herpesvirus (KSHV) tegument ... |
| _timestamp | 2026-05-19 13:17:06 |
| created | [InstanceEdit:9989214] Shamovsky, Veronica, 2026-05-19 |
| literatureReference | [LiteratureReference:9989208] KSHV-encoded ORF45 activates human NLRP1 inflammasome |
| text | The Kaposi’s sarcoma-associated herpesvirus (KSHV) tegument protein ORF45 activates the human NLRP1 inflammasome by functioning as a direct protein ligand. At a steady state, NLRP1 is maintained in an auto-inhibitory state through a critical interaction between its Linker1 region and the UPA subdomain of the C-terminal fragment. This Linker1–UPA association silences NLRP1 activity within two distinct complexes: a DPP9-independent NLRP1NT–NLRP1CT complex and a DPP9-dependent NLRP1FL–DPP9–NLRP1CT complex. ORF45 specifically targets the Linker1 region of NLRP1, with binding mediated by amino acids 300–332 of the viral protein. Upon binding to Linker1, ORF45 competes with and displaces the UPA subdomain from the Linker1–UPA complex. The disruption of this inhibitory interaction liberates the C-terminal fragment (NLRP1CT), which contains the essential CARD domain for inflammasome assembly. Once released, NLRP1CT undergoes self-oligomerization in the cytoplasm to recruit ASC and caspase-1, ultimately triggering pyroptotic cell death and cytokine release. Distinctively, this activation mechanism is protease-independent and does not rely on the proteasomal degradation of the N-terminal fragment (NLRP1NT). ORF45 is a virion-associated tegument protein of human herpesvirus 8 (HHV8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV)). HHV8 ORF45 directly interacts and activates the human NLR family pyrin domain-containing protein 1 (NLRP1) inflammasome (Yang X et al., 2022). Unlike standard triggers such as the enterovirus 3C protease, which leads to the proteasomal degradation of the N-terminal fragment (NT) of NLRP1, ORF45-mediated activation is protease-independent and is not blocked by proteasome inhibitors. At steady state, NLRP1 undergoes constitutive intramolecular autoproteolysis within its Function-to-find domain (FIIND) at the F1212–S1213 site (D'Osualdo A et al., 2011; Finger JA et al., 2012). This self-cleavage separates the protein into an inhibitory N-terminal (NT) fragment, NLRP1 (1–1212), and a C-terminal (CT) UPA-CARD fragment, that is competent for inflammasome activation. Following cleavage, these two fragments remain noncovalently associated, forming the NLRP1(1-1212):NLRP1(1213-1473) complex (D'Osualdo A et al., 2011; Finger JA et al., 2012). The interaction between the Linker1 region of NLRP1 located between the PYD and NACHT domains of NT and the UPA subdomain of CT fragment maintains NLRP1 in an autoinhibited state prior to activation (Yang X et al., 2022; Zhou J et al., 2025). through an interaction between the Linker1 region located between the PYD and NACHT domains in the N-terminal fragment (NT) of NLRP1 and the UPA subdomain within the function-to-find domain (FIIND) of the C-terminal fragment.maintaining NLRP1 in an autoinhibited state prior to activation By binding NLRP1 Linker1, KSHV ORF45 competitively displaces the NLRP1 UPA subdomain from its intramolecular autoinhibitory interaction, releasing the conformational constraint on the UPA–CARD CT fragment and permitting its dissociation and subsequent oligomerisation. This protease-independent mechanism does not generate the neo-N-terminal glycine required by the N-degron pathway and represents a distinct viral strategy for NLRP1 inflammasome activation ORF45 binds directly to the NLRP1 Linker1 region at the PYD–NACHT junction and competitively displaces the NLRP1 UPA subdomain from its intramolecular autoinhibitory engagement with Linker1, releasing the CT fragment. NLRP1 is maintained in an autoinhibitory state through an interaction between the Linker1 region located between the PYD and NACHT domains in the N-terminal fragment (NT) of NLRP1 and the UPA subdomain within the function-to-find domain (FIIND) of the C-terminal fragment. This Linker1–UPA interaction suppresses NLRP1 activation within the NLRP1(1-1212):NLRP1(1213-1473) complex, formed by the association of the N-terminal and the C-terminal fragments of NLRP1 and upon binding DPP9, forming a ternary complex consisting of DPP9, NLRP1(1-1212):NLRP1(1213-1473) and the C-terminal fragment NLRP1(1213-1473). ORF45 binds the Linker1 region of NLRP1. Binding of ORF45 competitively disrupts the Linker1–UPA interaction, effectively displacing the UPA subdomain and releasing the C-terminal fragment of NLRP1 from its autoinhibited state thereby enabling activation of NLRP1. Once liberated, the C-terminal fragment of NLRP1 (which contains the CARD domain) oligomerizes and serves as a platform for inflammasome assembly. Oligomerici NLRP1 CARD subsequently recruits the apoptosis-associated speck-like protein containing a CARD (ASC, encoded by the PYCARD gene) and caspase-1 (CASP1), forming large protein "specks". This assembly leads to the maturation of pro-inflammatory cytokines like IL-1β and the cleavage of gasdermin D (GSDMD), ultimately resulting in pyroptotic cell death. In contrast to canonical NLRP1 activation pathways, ORF45-mediated activation does not rely on the proteasomal degradation of the N-terminal fragment . This activation mechanism is conserved among primates, including rhesus and Saimiri macaques, but is absent in murine NLRP1b proteins, whose divergent Linker1 regions do not support ORF45 recognition. ORF45 as the first viral protein shown to activate the human NLRP1 inflammasome through a direct ligand-binding mechanism rather than the canonical pathway of protease-mediated degradation Direct Interaction and Protease-Independent Activation KSHV ORF45 functions as a direct protein ligand that binds to human NLRP1 to trigger activation. Unlike standard triggers such as the enterovirus 3C protease, which cause the proteasomal degradation of the NLRP1 N-terminal fragment (NLRP1NT), ORF45-mediated activation is protease-independent and is not blocked by proteasome inhibitors Steady-State Autoinhibition and Complex Formation At a steady state, human NLRP1 is maintained in an auto-inhibitory state through a critical interaction between its Linker1 region (located between the PYD and NACHT domains) and the UPA subdomain of the C-terminal fragment . This Linker1–UPA association silences NLRP1 activity within two distinct complexex DPP9-independent complexes: Formed by the association of the N-terminal fragment (NLRP1NT) and the C-terminal fragment (NLRP1CT) DPP9-dependent complexes: A ternary complex consisting of full-length NLRP1 (NLRP1FL), DPP9, and NLRP1CT In both scenarios, the Linker1–UPA interaction is essential for maintaining the inactive state Mechanism of ORF45-Mediated Activation ORF45 binds specifically to the Linker1 region of NLRP1 . This interaction is mediated by a determinant mapped to amino acids 300–332 of the ORF45 protein . Upon binding, ORF45 competitively disrupts the inhibitory Linker1–UPA interaction, effectively displacing the UPA subdomain and releasing the C-terminal fragment (NLRP1CT) from its auto-inhibited state Downstream Signaling and Pyroptosis Once liberated, the activated NLRP1CT (which contains the CARD domain) serves as a platform for inflammasome assembly . It recruits the adaptor protein ASC and caspase-1, forming large protein "specks" . This assembly leads to the maturation of pro-inflammatory cytokines like IL-1β and the cleavage of gasdermin D (GSDMD), ultimately resulting in pyroptotic cell death Nuclear Translocation vs. Degradation A defining feature of this non-canonical pathway is that NLRP1NT is not degraded . Instead, because ORF45 contains a nuclear localization sequence within its binding region, it carries the intact NLRP1NT fragment into the nucleus following activation . This nuclear relocalization is unique to ORF45 and is not seen in protease-triggered degradation pathways Evolutionary Conservation This activation mechanism is conserved among primates, including rhesus and Saimiri macaques . However, it is absent in murine NLRP1b proteins . This is due to the fact that rodents lack the specific Linker1 region found in primates, possessing a much shorter and divergent sequence that does not support ORF45 recognition |
| (summation) | [Reaction:9989216] HHV8 ORF45 binds NLRP1 [Homo sapiens] |
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