Mitigating Apoptotic and Inflammatory Signaling via Global Caspase Inhibition in Hibernating Ground Squirrels, Spermophilus lateralis
Mitigating Apoptotic and Inflammatory Signaling via Global Caspase Inhibition in Hibernating Ground Squirrels, Spermophilus lateralis
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DOI：
10.1086/722133
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发表时间：
2023-01-01
影响因子：
1.6
通讯作者：
van Breukelen, Frank
中科院分区：
文献类型：
--
作者：
Treat, Michael D.;Marlon, Anthony J.;van Breukelen, Frank
在大多数系统中，胱天蛋白酶级联在细胞应激期间被激活，并导致炎症和凋亡。冬眠者会经历压力，如极低的体温、心动过缓、可能的缺血和再灌注以及酸中毒。然而，广泛的炎症和细胞凋亡将代表一种与冬眠不相容的能量消耗。为了更好地了解冬眠期间的全球半胱天冬酶调节，我们采用系统水平的方法并分析了地松鼠肝脏中参与炎症（半胱天冬酶1、4、5、11和12）和细胞凋亡（半胱天冬酶2、6、7、8、9和10）途径的11种半胱天冬酶。蛋白质印迹显示在冬眠期间释放两种炎性（半胱天冬酶11和12）和两种凋亡（半胱天冬酶6和9）半胱天冬酶的活性形式（例如，p15是caspase 6最活跃的片段，在间歇性激发的动物中增加了8：2650：70倍）。我们使用特定的肽底物来询问四个看似激活的半胱天冬酶，并证明蛋白水解活性没有预期的增加。这四种半胱天冬酶的特异性靶点同样没有被切割，表明半胱天冬酶激活的起始可能在没有伴随的下游效应的情况下发生。类似地，我们没有发现基于线粒体外膜通透性的caspase 9信号传导的上游激活的证据。我们认为这些半胱天冬酶在冬眠期间似乎被激活后受到抑制。不完全的半胱天冬酶信号传导有效地减轻了冬眠期间广泛炎症和凋亡的诱导。
In most systems, the caspase cascade is activated during cellular stress and results in inflammation and apoptosis. Hibernators experience stressors such as extremely low body temperatures, bradycardia, possible ischemia and reperfusion, and acidosis. However, widespread inflammation and apoptosis would represent an energetic expense that is incompatible with hibernation. To better understand global caspase regulation during hibernation, we employed a systems-level approach and analyzed 11 caspases in ground squirrel liver that are involved in inflammatory (caspases 1, 4, 5, 11, and 12) and apoptotic (caspases 2, 6, 7, 8, 9, and 10) pathways. Western blots revealed liberation of active forms for two inflammatory (caspases 11 and 12) and two apoptotic (caspases 6 and 9) caspases during hibernation (e.g., p15, the most active fragment of caspase 6, increased 8:2650:70-fold in interboutaroused animals). We used specific peptide substrates to interrogate the four seemingly activated caspases and demonstrated no expected increases in proteolytic activity. Specific targets of these four caspases were similarly not cleaved, demonstrating that initiation of caspase activation may occur without concomitant downstream effects. Similarly, we found no evidence for upstream activation for caspase 9 signaling based on perme- abilization of the outer mitochondrial membrane. We contend that these caspases are suppressed after seeming activation during hibernation. Incomplete caspase signaling is effectively mitigating the induction of widespread inflammation and apoptosis during hibernation.