Infl ammasome is a large protein complex activated upon cellular stress or microbial infection,which triggers maturation of pro-inflammatory cytokines interleukin-1βand interleukin-18 through caspase-1 activation.Nod...Infl ammasome is a large protein complex activated upon cellular stress or microbial infection,which triggers maturation of pro-inflammatory cytokines interleukin-1βand interleukin-18 through caspase-1 activation.Nod-like receptor family protein 3(NLRP3)is the most character-ized infl ammasome activated by various stimuli.However,the mechanism of its activation is unclear and its exact cellular localization is still unknown.We examined the potential co-localization of NLRP3 infl ammasome with mi-tochondria and seven other organelles under adenosine triphosphate,nigericin or monosodium urate stimulation in mouse peritoneal macrophages using confocal micros-copy approach.Our results revealed that the activated endogenous apoptosis-associated speck-like protein containing a CARD(ASC)pyroptosome forms in the cyto-plasm and co-localizes with NLRP3 and caspase-1,but not with any of the organelles screened.This study indicates that the ASC pyroptosome universally localizes within the cytoplasm rather than with any specifi c organelles.展开更多
基金Acknowledgments We thank Drs Hua Gu （Columbia University, USA）, Weiguo Zhang （Duke University Medical Center, USA）, and Youhai H Chen （University of Pennsylvania, USA） for reviewing the manuscript and for suggestions, and Dr Ilia Voskoboinik （Peter MacCallum Cancer Centre, Australia） for providing the mouse perforin cDNA in pKS（＋） Bluescript. Ragl^-/- mice were gifts from Xiaolong Liu （Shanghai Institutes for Biological Sciences, China）. This work was supported by grants from the National Natural Science Foundation of China （30325018, 30530700, 30623003, and 30421005） and CAS project （KSCX1-YW-R-43）, grants from the National Key Project 973 （2006CB504300 and 2007CB512404）, grants from the Technology Commission of Shanghai Municipality （04DZ14902, 04DZ19108, 06DZ22032, 04DZ19112, 07XD14033, and 07DZ22916）, 863 key project （2006AA02A247）, and a grant from the E-institutes of Shanghai Universities Immunology Division.
文摘Perforin 是主要从事调停的形成毛孔的蛋白质目标 T 房间死亡并且被细胞毒素的 T 淋巴细胞(CTL ) 和自然漂亮房间采用。然而，它是否也在常规 CD4+ T 房间功能起一个作用，仍然保持不清楚。这里，我们报导那在 perforin 缺乏(PKO ) 老鼠， CD4+ T 房间是响应 T 的 hyperproliferative 房间受体(TCR ) 刺激。hyperproliferation 的这个特征被改进在房间分割并且在 IL-2 分泌物伴随。看起来， perforin 缺乏不在胸腺怒气和淋巴节点影响 T 房间开发。在 vivo， perforin 缺乏导致增加的抗原特定的 T 房间增长和抗体生产。而且， PKO 老鼠更产生试验性的自体免疫的眼色素层炎。探讨分子的机制，我们发现在 TCR 刺激以后，从 PKO 老鼠的 CD4+ T 房间显示增加的细胞内部的钙流动并且随后提高抄写因素 NFAT1 的激活。我们的结果显示 perforin 在由影响 TCR 依赖的 Ca2+ 发信号调整 CD4+ T 房间激活和有免疫力的反应起一个否定作用。
基金Acknowledgments We thank ProfYongjun Liu, Dangsheng Li and Yangxin Fu for helpful comments and Dr Sheri Skinner for reviewing the manuscript and for constructive suggestions. This work was supported by grants from the National Natural Science Foundation of China （30530700, 30623003, 30600568, 30721065, 90713044, 30600308, 30801011, 30870126） and CAS project （KSCX1-YW-R-43）, grant from SIBS project （2007KIP301）, grants from the Ministry of Science and Technology （2006CB504300, 2007CB512404, 2006AA02A247, 20072714）, the Technology Commission of Shanghai Municipality （88014199, 07DZ22916, 07XD14033, 064319034, 08431903004, 2008ZX10206, 08DZ2291703）, EU project （FP6-2005-SSP-5-B, SP5B-CT-2006-044161） and from the E-institutes of Shanghai Universities Immunology Division.
基金the National Basic Research Program(973 Program)(No.2013CB530504)the National Natural Science Foundation of China(Grant Nos.31230024,31030029,31100662,91029707 and 31170868)+4 种基金the Shanghai Natural Science Foundation(No.11ZR1442600)the National Ministry of Sci-ence and Technology(No.2007DFC31700)the National Science and Technology Major Project(Nos.2008ZX10004-002,2008ZX10002-014,2009ZX10004-105,2009ZX10004-016,2011ZX10004-001 and 2012ZX10002007)the Shanghai Pasteur Health Research Foundation(SPHRF2008001 and SPHRF2009001)the Novo Nordisk-CAS Research Foundation,the SA-SIBS Discovery Innovation Grant,the Li Kha Shing Foundation,and the 100 Talent Program of the Chinese Academy of Sciences(to G.M.).
文摘Infl ammasome is a large protein complex activated upon cellular stress or microbial infection,which triggers maturation of pro-inflammatory cytokines interleukin-1βand interleukin-18 through caspase-1 activation.Nod-like receptor family protein 3(NLRP3)is the most character-ized infl ammasome activated by various stimuli.However,the mechanism of its activation is unclear and its exact cellular localization is still unknown.We examined the potential co-localization of NLRP3 infl ammasome with mi-tochondria and seven other organelles under adenosine triphosphate,nigericin or monosodium urate stimulation in mouse peritoneal macrophages using confocal micros-copy approach.Our results revealed that the activated endogenous apoptosis-associated speck-like protein containing a CARD(ASC)pyroptosome forms in the cyto-plasm and co-localizes with NLRP3 and caspase-1,but not with any of the organelles screened.This study indicates that the ASC pyroptosome universally localizes within the cytoplasm rather than with any specifi c organelles.
