Interaction of pyrin with 14.3.3 in an Isoform‐specific and phosphorylation‐dependent manner regulates its translocation to the nucleus

Abstract

Objective. Pyrin, the familial Mediterranean fever gene product, exists in several isoforms of unknown functions. The recombinant full-length isoform (pyrin.fl) is cytoplasmic, whereas an alternatively spliced isoform lacking exon 2 (pyrin.⌬Ex2) concentrates in the nucleus. Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types. To understand pyrin-dependent biologic pathways and to decipher the mechanisms accounting for such different patterns of subcellular compartmentalization, binding partners and posttranslational modifications of pyrin were assessed. Conclusion. These results disclose the role played by 14.3.3 in the regulation of the subcellular compartmentalization of pyrin in a phosphorylation-and isoform-dependent manner. They also reconcile the observations made in vitro with those made in vivo, while providing a direct link between 14.3.3-dependent pathways and pyrin.Pyrin, also called marenostrin, is the product of the MEFV gene involved in familial Mediterranean fever (FMF) (MIM no. 249100) (1,2). FMF is an autosomal recessive condition that primarily affects populations of Mediterranean extraction and is characterized by recurrent episodes of fever and serosal inflammation, manifested by sterile peritonitis, arthritis, and/or pleurisy. MEFV, which is composed of 10 coding exons and spans 15 kb on the 16p13.3 region, is expressed mainly in granulocytes and monocytes (3,4). Although the physiologic role of the pyrin/marenostrin protein is yet to be elucidated, the identification of a domain (called pyrin, or PYD) in its N-terminal region has revealed the existence of an expanding family of related PYDcontaining proteins involved in both inflammatory and

Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation

“…S1A). Interestingly, 14-3-3 was identified more than 10 y ago in a Pyrin yeast two-hybrid screen, but its functional significance has not been known (32). The 14-3-3 proteins are highly conserved from yeast to mammals and are abundantly expressed in eukaryotic cells (33).…”

Familial Mediterranean fever—A review

“…38 Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types. 39 …”

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

“…It appears that according to the cell type or to the spliced isoform studied, Pyrin can be localized diffusely or as specks, in the cytoplasm, but also in the nucleus. [15][16][17][18][19][20] Pyrin contains at the N-terminus a Pyrin domain (PYD), a member of the death effector-fold domains, [21][22][23] two B-boxes and a coiled-coil domain (BBCC), as well as a SPRY domain (also called B30.2 domain). The PYD found in Pyrin is also present in NALP proteins.…”