PMID- 30592629 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20200728 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 33 IP - 3 DP - 2019 Mar TI - Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation. PG - 4547-4558 LID - 10.1096/fj.201801585R [doi] AB - Endoplasmic reticulum (ER)-Golgi vesicle trafficking plays a pivotal role in the conventional secretory pathway of many cytokines; however, the precise release mechanism of a major inflammasome mediator, IL-1beta, is not thought to follow the conventional ER-Golgi route and remains elusive. Here, we found that perturbation of ER-Golgi trafficking by brefeldin A (BFA) treatment attenuated nucleotide-binding oligomerization domain-like receptor family, pyrin-domain-containing 3 (NLRP3) inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). BFA treatment inhibited NLRP3-mediated inflammasome assembly and caspase-1 activation but did not block IL-1beta secretion from BMDMs following BFA administration after NLRP3 inflammasome activation. Consistently, short-hairpin RNA-dependent knockdown of BFA-inhibited guanine nucleotide-exchange protein 1 (BIG1), a molecular target of BFA and an initiator of Golgi-specific vesicle trafficking, abolished NLRP3-dependent apoptosis-associated speck-like protein containing a caspase-recruitment domain oligomerization and caspase-1 activation in BMDMs. Similarly, knockdown of Golgi-specific BFA-resistance guanine nucleotide exchange factor 1, another target of BFA, clearly attenuated NLRP3-mediated caspase-1 activation in BMDMs. Mechanistically, inhibition of BIG1-mediated vesicle trafficking did not impair NLRP3-activating signal 2-promoted events, such as potassium efflux and mitochondrial rearrangement, but caused significant impairment of signal 1-triggered priming steps, including NF-kappaB-mediated pathways. These data suggest that BFA-targeted vesicle trafficking at the Golgi contributes to activation of the NLRP3 inflammasome signaling.-Hong, S., Hwang, I., Gim, E., Yang, J., Park, S., Yoon, S.-H., Lee, W.-W., Yu, J.-W. Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation. FAU - Hong, Sujeong AU - Hong S AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Hwang, Inhwa AU - Hwang I AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Gim, Eunji AU - Gim E AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Yang, Jungmin AU - Yang J AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Park, Sangjun AU - Park S AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Yoon, Sung-Hyun AU - Yoon SH AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. FAU - Lee, Won-Woo AU - Lee WW AD - Department of Biomedical Sciences and Seoul National University College of Medicine, Seoul, South Korea. AD - Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea. FAU - Yu, Je-Wook AU - Yu JW AD - Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; and. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181228 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (ARFGEF1 protein, human) RN - 0 (Arfgef1 protein, mouse) RN - 0 (Gbf1 protein, mouse) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 20350-15-6 (Brefeldin A) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 3.4.22.36 (Casp1 protein, mouse) RN - EC 3.4.22.36 (Caspase 1) RN - RWP5GA015D (Potassium) SB - IM MH - Adenosine Triphosphate/pharmacology MH - Animals MH - Brefeldin A/*pharmacology MH - Caspase 1/*metabolism MH - Endoplasmic Reticulum/*drug effects/metabolism MH - Enzyme Activation/drug effects MH - Golgi Apparatus/*drug effects/metabolism MH - Guanine Nucleotide Exchange Factors/antagonists & inhibitors/deficiency/metabolism MH - Humans MH - Inflammasomes/drug effects/*physiology MH - Interleukin-1beta/biosynthesis MH - Macrophages/*drug effects/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mitochondria/drug effects/ultrastructure MH - NLR Family, Pyrin Domain-Containing 3 Protein/deficiency/genetics/*physiology MH - Potassium/metabolism MH - Protein Transport/*drug effects MH - Specific Pathogen-Free Organisms MH - THP-1 Cells OTO - NOTNLM OT - BFA OT - BIG1 OT - IL-1beta secretion OT - inflammasome EDAT- 2018/12/29 06:00 MHDA- 2020/05/12 06:00 CRDT- 2018/12/29 06:00 PHST- 2018/12/29 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] PHST- 2018/12/29 06:00 [entrez] AID - 10.1096/fj.201801585R [doi] PST - ppublish SO - FASEB J. 2019 Mar;33(3):4547-4558. doi: 10.1096/fj.201801585R. Epub 2018 Dec 28.