Pyrin

Function

Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation. However, it can also have a positive effect in the inflammatory pathway, acting as an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production. Together with AIM2, also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). It is required for PSTPIP1-induced PYCARD/ASC oligomerization and inflammasome formation. Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization.

Classification

Family (Pfam)

PF13765 PRY, PF02758 PYRIN, PF00622 SPRY, PF00643 zf-B_box

InterPro

B30.2/SPRY, B30.2/SPRY_sf, Butyrophylin_SPRY, ConA-like_dom_sf, DAPIN, DEATH-like_dom_sf, PRY, SPRY_dom, TRIM/RBCC, Znf_B-box

Functional cluster

Immunoglobulin & Immune-Response Proteins

Experimental structures · PDB · 11

• 2MPC NMR
• 2WL1 X-ray 1.35A
• 4CG4 X-ray 2.40A
• 8C28 X-ray 1.60A
• 8C2Y X-ray 1.46A
• 8C30 X-ray 1.40A
• 8SDJ X-ray 2.40A
• 9R6Y X-ray 1.26A
• 9R70 X-ray 1.50A
• 9R73 X-ray 1.44A
• 9R74 X-ray 2.00A

A predicted model is available from AlphaFold.

Gene Ontology · 30

• GO:0005776 autophagosome
• GO:0005737 cytoplasm
• GO:0031410 cytoplasmic vesicle
• GO:0005829 cytosol
• GO:0030027 lamellipodium
• GO:0005874 microtubule
• GO:0005875 microtubule associated complex
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0001726 ruffle
• GO:0003779 actin binding
• GO:0042802 identical protein binding
• GO:0061630 ubiquitin protein ligase activity
• GO:0008270 zinc ion binding
• GO:0006954 inflammatory response
• GO:0045087 innate immune response
• GO:1900016 negative regulation of cytokine production involved in inflammatory response
• GO:0050728 negative regulation of inflammatory response
• GO:0032691 negative regulation of interleukin-1 beta production
• GO:0032695 negative regulation of interleukin-12 production
• GO:0071641 negative regulation of macrophage inflammatory protein 1 alpha production
• GO:1900226 negative regulation of NLRP3 inflammasome complex assembly
• GO:0002221 pattern recognition receptor signaling pathway
• GO:0010508 positive regulation of autophagy
• GO:0032731 positive regulation of interleukin-1 beta production
• GO:1904270 pyroptosome complex assembly
• GO:0070269 pyroptotic inflammatory response
• GO:0010468 regulation of gene expression
• GO:0032651 regulation of interleukin-1 beta production
• GO:0034341 response to type II interferon

Disease associations

• familial Mediterranean fever, autosomal dominant MONDO:0007601
• autosomal recessive familial Mediterranean fever MONDO:0009572
• sweet syndrome MONDO:0011959

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Pyrin 0.92
• Pyrin 0.91
• E3 ubiquitin-protein ligase TRIM21 0.90
• E3 ubiquitin-protein ligase TRIM21 0.90
• Zinc finger protein RFP 0.90
• Zinc finger protein RFP 0.89
• E3 ubiquitin-protein ligase TRIM15 0.89
• E3 ubiquitin-protein ligase TRIM15 0.89
• E3 ubiquitin-protein ligase TRIM15 0.89
• E3 ubiquitin-protein ligase TRIM17 0.89
• E3 ubiquitin-protein ligase TRIM15 0.89
• Tripartite motif-containing protein 10 0.89

Co-cited proteins · studied together in the literature

• Proline-serine-threonine phosphatase-interacting protein 1 4 shared papers
• Apoptosis-associated speck-like protein containing a CARD 2 shared papers
• Zinc finger protein 200 1 shared papers
• Olfactory receptor 1F1 1 shared papers
• Caspase-1 1 shared papers
• Actin-related protein 3 1 shared papers
• NF-kappa-B inhibitor alpha 1 shared papers
• Vasodilator-stimulated phosphoprotein 1 shared papers
• Caspase-5 1 shared papers
• Transcription factor p65 1 shared papers
• NACHT, LRR and PYD domains-containing protein 2 1 shared papers
• NACHT, LRR and PYD domains-containing protein 1 2 shared papers

Literature · 41 cited papers

• A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever. Ann. Rheum. Dis. · 2017
• Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci. Transl. Med. · 2016
• TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J. Cell Biol. · 2015
• Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene · 2014
• MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann. Rheum. Dis. · 2014
• Prevalence of known mutations and a novel missense mutation (M694K) in the MEFV gene in a population from the Eastern Anatolia Region of Turkey. Gene · 2012
• The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever. J. Mol. Biol. · 2009
• Pyrin Modulates the Intracellular Distribution of PSTPIP1. PLoS ONE · 2009
• Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp. Biol. Med. (Maywood) · 2009
• The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood · 2008
• Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol. Cell · 2007
• The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ. · 2007
• … and 29 more in the literature graph