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ORIGINAL RESEARCH ARTICLE

Pyrin and ASC Co-Localize to Cellular Sites that Are Rich in Polymerizing Actin

Andrea L. Waite^*, Philip Schaner, Chunbo Hu^*, Neil Richards^*, Banu Balci-Peynircioglu^*,, Arthur Hong^*, Michelle Fox^* and Deborah L. Gumucio^*,1

^* University of Michigan, Department of Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200; University of Alabama at Birmingham, Division of Radiology/Oncology, Birmingham, Alabama 35294; Hacettepe University, Faculty of Medicine, Department of Medical Biology, Ankara, 06100 Turkey

To whom requests for reprints should be addressed at ¹ Department of Cell and Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, Box 2200, Ann Arbor, MI 48109-2200. E-mail: dgumucio{at}umich.edu

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV locus, which encodes the protein pyrin. While it is known that pyrin is expressed in myeloid cells and several fibroblastic cell types, the exact function of pyrin in these cells and the mechanism underlying the pathological effect of pyrin mutations have yet to be revealed. Here, we document that in migrating human monocytes, pyrin protein is dramatically polarized at the leading edge, where it co-localizes with polymerizing actin. ASC (Apoptosis-associated Speck protein with CARD domain), a known pyrin-interacting protein and a critical component of the inflamma-some, is also located at the leading edge in migrating monocytes. Similarly, both pyrin and ASC concentrate in dynamically polymerizing actin-rich tails generated by Listeria monocytogenes. Pyrin’s B-box and coiled-coil region is required for its association with Listeria tails. Pyrin also binds, with low affinity and via the same domains, to actin, VASP, and Arp3. Though disease-causing mutations in pyrin do not appear to alter its localization to the leading edge or to Listeria rocket tails, they could potentially have important functional consequences in the context of processes such as migration and cell synapse formation. The co-localization of pyrin and ASC together at such sites may provide an important link between cytoskeletal signaling and inflammasome function.

Key Words: pyrin • familial Mediterranean fever • actin • ASC

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