The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages.
The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages.
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DOI：
10.4049/jimmunol.1501662
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Chan FK
中科院分区：
文献类型：
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作者：
Moriwaki K;Farias Luz N;Balaji S;De Rosa MJ;O'Donnell CL;Gough PJ;Bertin J;Welsh RM;Chan FK
细胞因子IL-1β与许多病理性炎症状态密切相关。成熟的IL-1β分泌需要炎性小体裂解。最近的证据表明，许多细胞死亡信号衔接子在炎性小体活动中具有调节作用。这些包括凋亡诱导剂FADD和半胱天冬酶8，以及坏死性凋亡激酶受体相互作用蛋白激酶1（RIPK 1）和RIPK 3。磷酸甘油酸酯激酶家族成员5（PGAM 5）是一种线粒体磷酸酶，据报道其在RIPK 3下游起作用以促进坏死性凋亡和IL-1β分泌。为了探究PGAM 5的生物学功能，我们产生了Pgam 5 −/−小鼠。我们发现Pgam 5 −/−小鼠与野生型同窝小鼠相比体型较小，雄性Pgam 5 −/−小鼠以亚孟德尔比例出生。尽管存在这些生长和存活缺陷，但Pgam 5 −/−细胞对凋亡和坏死性凋亡的多种诱导剂反应正常。相反，我们发现PGAM 5对于响应NLRP 3和AIM 2炎性体激动剂的IL-1β分泌至关重要。此外，水泡性气孔病病毒（VSV）诱导的IL-1β分泌在Pgam 5 −/−骨髓源性巨噬细胞（BMDM）中受损，但在Ripk 3 −/− BMDM中未受损，表明PGAM 5的功能独立于RIPK 3，以促进炎性小体激活。从机制上讲，PGAM 5促进ASC聚合，维持线粒体完整性，以及响应炎性信号的最佳ROS产生。因此，PGAM 5是炎性小体和半胱天冬酶1活性的新调节剂，其功能独立于RIPK 3。
The cytokine IL-1β is intimately linked to many pathological inflammatory conditions. Mature IL-1β secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1β secretion. To interrogate the biological function of PGAM5, we generated Pgam5−/− mice. We found that Pgam5−/− mice were smaller in size compared with wild type littermates, and male Pgam5−/− mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5−/− cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1β secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus (VSV)-induced IL-1β secretion was impaired in Pgam5−/− bone marrow derived macrophages (BMDMs), but not in Ripk3−/− BMDMs, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal ROS production in response to inflammasome signals. Hence, PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3.