PMID- 25713392 OWN - NLM STAT- MEDLINE DCOM- 20150511 LR - 20201209 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 112 IP - 10 DP - 2015 Mar 10 TI - Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration. PG - 3056-61 LID - 10.1073/pnas.1501554112 [doi] AB - Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naive T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function. FAU - Krishnaswamy, Jayendra Kumar AU - Krishnaswamy JK AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Singh, Arpita AU - Singh A AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Gowthaman, Uthaman AU - Gowthaman U AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Wu, Renee AU - Wu R AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Gorrepati, Pavane AU - Gorrepati P AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Sales Nascimento, Manuela AU - Sales Nascimento M AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Gallman, Antonia AU - Gallman A AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Liu, Dong AU - Liu D AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Rhebergen, Anne Marie AU - Rhebergen AM AD - Immunobiology and. FAU - Calabro, Samuele AU - Calabro S AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Xu, Lan AU - Xu L AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Ranney, Patricia AU - Ranney P AD - Departments of Laboratory Medicine and Immunobiology and. FAU - Srivastava, Anuj AU - Srivastava A AD - Computational Sciences, The Jackson Laboratory, Bar Harbor, ME 04609; FAU - Ranson, Matthew AU - Ranson M AD - Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; FAU - Gorham, James D AU - Gorham JD AD - Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; FAU - McCaw, Zachary AU - McCaw Z AD - National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; FAU - Kleeberger, Steven R AU - Kleeberger SR AD - National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; FAU - Heinz, Leonhard X AU - Heinz LX AD - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; FAU - Muller, Andre C AU - Muller AC AD - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; FAU - Bennett, Keiryn L AU - Bennett KL AD - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; FAU - Superti-Furga, Giulio AU - Superti-Furga G AD - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; FAU - Henao-Mejia, Jorge AU - Henao-Mejia J AD - Institute for Immunology, Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; FAU - Sutterwala, Fayyaz S AU - Sutterwala FS AD - Inflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52241; and. FAU - Williams, Adam AU - Williams A AD - The Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032. FAU - Flavell, Richard A AU - Flavell RA AD - Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; stephanie.eisenbarth@yale.edu richard.flavell@yale.edu. FAU - Eisenbarth, Stephanie C AU - Eisenbarth SC AD - Departments of Laboratory Medicine and Immunobiology and stephanie.eisenbarth@yale.edu richard.flavell@yale.edu. LA - eng SI - SRA/SRR1792904 GR - P30 ES005605/ES/NIEHS NIH HHS/United States GR - R01 AI108829/AI/NIAID NIH HHS/United States GR - P30 DK045735/DK/NIDDK NIH HHS/United States GR - Howard Hughes Medical Institute/United States GR - K08 AI085038/AI/NIAID NIH HHS/United States GR - R01 AI087630/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150223 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Carrier Proteins) RN - 0 (Dock8 protein, mouse) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (NLRP10 protein, human) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Apoptosis Regulatory Proteins MH - Carrier Proteins/genetics/*physiology MH - Cell Movement/*genetics MH - Dendritic Cells/*immunology MH - Guanine Nucleotide Exchange Factors/genetics/*physiology MH - Lymphocyte Activation MH - Mice MH - Mice, Inbred C3H MH - Mice, Knockout MH - Point Mutation PMC - PMC4364188 OTO - NOTNLM OT - C3H/HeJ OT - CDC42 OT - DOCK8 OT - NLRP10 OT - dendritic cell COIS- The authors declare no conflict of interest. EDAT- 2015/02/26 06:00 MHDA- 2015/05/12 06:00 PMCR- 2015/09/10 CRDT- 2015/02/26 06:00 PHST- 2015/02/26 06:00 [entrez] PHST- 2015/02/26 06:00 [pubmed] PHST- 2015/05/12 06:00 [medline] PHST- 2015/09/10 00:00 [pmc-release] AID - 1501554112 [pii] AID - 201501554 [pii] AID - 10.1073/pnas.1501554112 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3056-61. doi: 10.1073/pnas.1501554112. Epub 2015 Feb 23.