NLRP11

NLRP11 is a primate-specific NLR-family protein that operates at the interface of innate immune signaling, acting both as a negative regulator of antiviral/inflammatory signaling and as a positive sensor and scaffold for inflammasome assembly (PMID:29215004, PMID:35624206, PMID:37478192). As a brake on signaling, NLRP11 recruits the E3 ubiquitin ligase RNF19A to drive K48-linked polyubiquitination and proteasomal degradation of TRAF6, attenuating NF-κB and MAPK output and proinflammatory cytokine production (PMID:29215004); upon viral infection it is induced by type I IFN, translocates to mitochondria, and uses MAVS as a platform to degrade TRAF6 and dampen type I IFN responses (PMID:29097393). Through its LRR domain it binds the RNA helicase DDX3X and blocks IKKε-mediated DDX3X phosphorylation, providing a second route to suppress type I IFN induction (PMID:34054816). In a contrasting positive role, NLRP11 is an essential component of the human NLRP3 inflammasome, interacting with NLRP3 and ASC through a PYD-dependent mechanism required for inflammasome assembly, caspase-1 activation, pyroptosis, and IL-1β/IL-18 release (PMID:35624206). NLRP11 additionally functions as a cytosolic pattern-recognition receptor that directly binds LPS and assembles an ASC-independent complex with caspase-4 to drive non-canonical inflammasome activation, gasdermin-D cleavage, and pyroptosis during intracellular Gram-negative and mycobacterial infection, a function dependent on its NACHT and LRR domains rather than its PYD (PMID:37478192, PMID:40272180, PMID:41676729). Beyond immunity, NLRP11 bridges the acetyltransferase KAT7 to vimentin to promote vimentin K104 acetylation and epithelial-mesenchymal transition in lung adenocarcinoma (PMID:37424170).

1. 2017 High

   Established that NLRP11 is a negative regulator of innate immune signaling by defining how it triggers degradation of a central signaling hub.

   Evidence Co-IP, ubiquitination assays, and knockdown/knockout with NF-κB/MAPK and cytokine readouts showing NLRP11 recruits RNF19A to drive K48-linked ubiquitination and proteasomal degradation of TRAF6

   PMID:29215004

   Open questions at the time

   • Does not define which upstream stimuli engage the NLRP11–RNF19A module
   • Structural basis of TRAF6 selection not resolved
2. 2017 Medium

   Extended the negative-regulatory role to antiviral signaling by localizing NLRP11 to a specific platform.

   Evidence Co-IP, subcellular fractionation, and knockdown with IFN/apoptosis readouts showing IFN-induced NLRP11 translocates to mitochondria, binds MAVS, and degrades TRAF6 to limit type I IFN

   PMID:29097393

   Open questions at the time

   • Mechanism of mitochondrial translocation unknown
   • Relationship to the RNF19A-mediated TRAF6 degradation pathway not integrated
3. 2020 Medium

   Identified an inflammasome-independent immunosuppressive function in B lymphoblasts, broadening NLRP11 roles beyond classical inflammasome biology.

   Evidence siRNA knockdown, endogenous NLRP11–ASC Co-IP, caspase-1 activity assay, and T cell co-culture cytokine assays showing adenosine-induced NLRP11 binds ASC without activating caspase-1 and suppresses Th cytokines

   PMID:32832566

   Open questions at the time

   • Molecular basis of T cell suppression not defined
   • How NLRP11–ASC binding avoids caspase-1 activation unresolved
4. 2021 Medium

   Mapped a second IFN-suppressive mechanism via direct interaction with a helicase, and linked the LRR domain to inflammasome control.

   Evidence Co-IP, LC-MS/MS, domain-deletion mutants, phosphorylation and caspase-1 assays showing LRR-dependent binding of DDX3X that blocks IKKε-mediated DDX3X phosphorylation and dampens NLRP3-driven caspase-1 activation

   PMID:34054816

   Open questions at the time

   • DDX3X sequestration model not directly demonstrated
   • Reconciliation with NLRP11's positive role in NLRP3 inflammasome unresolved
5. 2022 High

   Reframed NLRP11 as an essential positive component of the human NLRP3 inflammasome, identifying the domain required.

   Evidence CRISPR knockout, reciprocal Co-IP, ASC polymerization, caspase-1 and pyroptosis assays, and PYD-deletion rescue showing PYD-dependent interaction with NLRP3 and ASC is required for inflammasome assembly

   PMID:35624206

   Open questions at the time

   • Does not reconcile the positive NLRP3 role with the earlier suppressive findings
   • Structural detail of the NLRP11–NLRP3–ASC complex absent
6. 2023 High

   Defined NLRP11 as a cytosolic LPS sensor that initiates non-canonical inflammasome activation via caspase-4.

   Evidence CRISPR knockout, direct LPS binding assay, Co-IP and gel-filtration of an NLRP11–caspase-4 complex, plus infection/electroporation functional assays in human macrophages

   PMID:37478192

   Open questions at the time

   • Stoichiometry and architecture of the NLRP11–caspase-4 complex not solved
   • How LPS binding triggers complex assembly unclear
7. 2023 Medium

   Uncovered a non-immune oncogenic function as a scaffold linking an acetyltransferase to a cytoskeletal substrate.

   Evidence Co-IP, site-specific acetylation assays with K104Q mimetic, localization, and in vitro/in vivo tumor assays showing NLRP11 bridges KAT7 to vimentin to promote K104 acetylation and EMT

   PMID:37424170

   Open questions at the time

   • Whether the EMT function relates to immune signaling domains not addressed
   • Regulation of KAT7 cytoplasmic relocalization by NLRP11 unresolved
8. 2025 High

   Dissected the domain requirements distinguishing canonical from non-canonical inflammasome roles and broadened pathogen scope.

   Evidence CRISPR-defined ΔNACHT/ΔLRR and ΔPYD mutants with caspase-4 and NLRP3 activation readouts across Shigella, M. tuberculosis, and M. kansasii infection

   PMID:40272180

   Open questions at the time

   • Apparent discrepancy with PYD-dependence reported for NLRP3 activation not fully reconciled
   • Ligand recognized in mycobacteria not identified
9. 2026 Medium

   Resolved the molecular requirements for NLRP11-driven non-canonical pyroptosis at the level of caspase-4 contacts and catalysis.

   Evidence Mutational analysis, Co-IP, LPS binding, and gasdermin-D cleavage/pyroptosis assays in ASC-deficient cells showing a conserved CASP4 p20 residue, NLRP11–CASP4 binding, LPS binding, and CASP4 catalysis are each required (preprint)

   PMID:41676729

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Structural model of the NLRP11–CASP4 interface not determined

• How NLRP11's opposing roles—TRAF6/IFN suppression versus inflammasome promotion—are switched within a single cell remains unresolved.
• No unifying model integrates the negative signaling-regulator and positive inflammasome-sensor functions
• No structural data for any NLRP11 complex
• Determinants of stimulus- or cell-type-specific pathway choice unknown