Coordinate regulation of autophagy and apoptosis in T cells by death effectors FADD or foundation
Coordinate regulation of autophagy and apoptosis in T cells by death effectors FADD or foundation
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DOI：
10.4161/auto.5.2.7512
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发表时间：
2009-02-16
期刊：
影响因子：
13.3
通讯作者：
Walsh, Craig M.
中科院分区：
文献类型：
--
作者：
Bell, Bryan D.;Walsh, Craig M.
在免疫应答期间，微生物和肿瘤抗原的特异性识别导致淋巴细胞的快速增殖。一旦免疫挑战被消除，这些淋巴细胞中的绝大多数必须通过凋亡被去除。细胞死亡对于自身反应性或慢性激活的淋巴细胞的缺失也是至关重要的，以防止宿主中自身免疫的发展。这些过程高度依赖于死亡受体（DR），TNF受体家族的分子。虽然这些DR促进细胞凋亡，但DR信号的干扰自相矛盾地干扰了快速淋巴细胞增殖。最近，我们发现，T细胞缺乏Fas相关蛋白与死亡结构域（FADD）或caspase-8（caspase-8）的功能，这两个必不可少的DR诱导的细胞凋亡，屈服于自噬的过度激活和死亡，通过非凋亡形式的细胞死亡，而不是增殖后有丝分裂原刺激。我们观察到FADD，Casp 8和丝氨酸/苏氨酸激酶RIPK 1的招聘到含有Atg 5，Atg 12和Atg 16 L的复合物，这表明早期自噬体的产生导致激活Casp 8的复合物的组装。由于阻断RIPK 1或干扰自噬信号传导抑制了这种替代性死亡过程，因此我们提出，在没有半胱天冬酶活性的情况下诱导的过度活跃的自噬导致依赖于RIPK 1酶功能的坏死样死亡。在此，我们总结了这些发现，并推测自噬的意义和手段，通常是在增殖淋巴细胞激活。
During an immune response, specific recognition of microbial and tumor antigens leads to the rapid proliferation of lymphocytes. Once the immunological challenge is eliminated, the vast majority of these lymphocytes must be removed via apoptosis. Cell death is also vital for the deletion of autoreactive or chronically activated lymphocytes to prevent the development of autoimmunity in the host. Such processes are highly dependent on death receptors (DRs), molecules of the TNF receptor family. While these DRs promote apoptosis, interference with DR signaling paradoxically interferes with rapid lymphocyte proliferation. Recently, we discovered that T cells lacking Fas-Associated protein with Death Domain (FADD) or caspase-8 (casp8) function, both essential for DR-induced apoptosis, succumb to hyperactivation of autophagy and die through a nonapoptotic form of cell death rather than proliferating after mitogen stimulation. We observed recruitment of FADD, casp8 and serine/threonine kinase RIPK1 to complexes containing Atg5, Atg12 and Atg16L, suggesting that the generation of early autophagosomes leads to the assembly of complexes that activate casp8. Because blockade of RIPK1 or interference with autophagic signaling inhibited this alternative death process, we propose that hyperactive autophagy induced in the absence of caspase activity leads to a necrosis-like form of death that depends on RIPK1 enzymatic function. Herein, we summarize these findings and speculate on the significance and means by which autophagy is normally activated in proliferating lymphocytes.