美国科学家近日研究发现，破坏一种蠕虫的SRP-6蛋白能加速其细胞的坏死过程。这一发现有助于科学家更好地理解坏死（necrosis）——细胞死亡的方式之一，并找到对抗相关疾病的方法。相关论文发表在9月21日的《细胞》上。  

   细胞死亡的方式有多种，细胞凋亡（apoptosis）和坏死是比较典型的两种。细胞凋亡是在某些生理或病理条件下，细胞受到某种刺激后，为了生物体的利益考虑，细胞主动参与并按一定程序发生的自杀性死亡。坏死则与此不同，这种情况下，细胞并不会主动死亡，但是一些因素，比如失血、缺氧等，都会使其膨胀并发生爆裂。一些科学家已经发现有些方法能加速坏死过程，但是关于它能否被停止却一直没有弄清。  

   在最新的研究中，美国匹兹堡大学的分子生物学家Gary  Silverman和同事将研究重点放在了serpins蛋白，这种蛋白的一部分能够帮助控制血液凝结和炎症。研究小组破坏了蠕虫体内编码SRP-6（serpins的一种）的基因，结果发现，这些蠕虫放进常温水中后会快速死亡。进一步的研究发现，蠕虫死亡的原因在于压力响应机制出错了，它们已不能向正常蠕虫那样调节细胞内的液体量，它们细胞内的溶酶体（lysosomes）已经爆裂。将破坏了SRP-6的蠕虫暴露于其它压力条件下，比如高温、缺氧等，也会得到类似的结果。研究人员表示，破坏了SRP-6的蠕虫无法像正常蠕虫那样修复受损的溶酶体。此次实验表明了，SRP-6的作用在于防止蠕虫细胞坏死和溶酶体破裂。  

   美国纽约州立大学石溪分校的分子生物学家Wei-Xing  Zong认为，这项研究真是让人吃惊，人们可能从没有想过坏死也能被控制。  

   美国Burnham医学研究所的Guy  Salvesen表示，此项研究非常重要，查明坏死的分子路径将有助于研究人员找到对抗相关疾病的方法。不过他又提醒说，由于尚不清楚坏死能在多大程度上被控制，所以此次实验结果能否应用于人类还有待更进一步的研究。（科学网）

原始出处:

Cell, Vol 130, 1108-1119, 21 September 2007

Article

An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury

Cliff J. Luke,1 Stephen C. Pak,1 Yuko S. Askew,1 Terra L. Naviglia,1 David J. Askew,1 Shila M. Nobar,1 Anne C. Vetica,1 Olivia S. Long,1 Simon C. Watkins,2,3 Donna B. Stolz,2,3 Robert J. Barstead,4 Gary L. Moulder,4 Dieter Brömme,5 and Gary A. Silverman1,2,

1 UPMC Newborn Medicine Program, Departments of Pediatrics Children's Hospital of Pittsburgh and Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA
2 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, S233 BST, Pittsburgh, PA 15261, USA
3 Center for Biologic Imaging, University of Pittsburgh School of Medicine, 3500 Terrace Street, S233 BST, Pittsburgh, PA 15261, USA
4 Department of Molecular and Cell Biology, Oklahoma Medical Research Foundation 825 NE 13th Street, Oklahoma City, OK 73104, USA
5 University of British Columbia, Faculty of Dentistry, 2350 Health Sciences Mall, Life Sciences Institute, Room 4558, Vancouver, British Columbia V6T 1Z3, Canada

Corresponding author
Gary A. Silverman
gsilverman@mail.magee.edu

Extracellular serpins such as antithrombin and α1-antitrypsin are the quintessential regulators of proteolytic pathways. In contrast, the biological functions of the intracellular serpins remain obscure. We now report that the C. elegans intracellular serpin, SRP-6, exhibits a prosurvival function by blocking necrosis. Minutes after hypotonic shock, srp-6 null animals underwent a catastrophic series of events culminating in lysosomal disruption, cytoplasmic proteolysis, and death. This newly defined hypo-osmotic stress lethal (Osl) phenotype was dependent upon calpains and lysosomal cysteine peptidases, two in vitro targets of SRP-6. By protecting against both the induction of and the lethal effects from lysosomal injury, SRP-6 also blocked death induced by heat shock, oxidative stress, hypoxia, and cation channel hyperactivity. These findings suggest that multiple noxious stimuli converge upon a peptidase-driven, core stress response pathway that, in the absence of serpin regulation, triggers a lysosomal-dependent necrotic cell death routine.

                                                       摘自《生物谷》