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经典凋亡衔接蛋白 FADD 调节急性淋巴细胞白血病的糖酵解能力。

The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia.

机构信息

The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

School of Biopharmacy, China Pharmaceutical University, Nanjing, China.

出版信息

Int J Biol Sci. 2022 May 1;18(8):3137-3155. doi: 10.7150/ijbs.68016. eCollection 2022.

DOI:10.7150/ijbs.68016
PMID:35637951
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9134909/
Abstract

The Fas-associated death domain (FADD) has long been regarded as a crucial adaptor protein in the extrinsic apoptotic pathway. Despite the non-apoptotic function of FADD is gradually being discovered and confirmed, its corresponding physiological and pathological significance is still unclear. Based on the database of GWAS catalog and GTEx Portal, 17 SNPs associated with leukemia susceptibility were found to be linked to FADD expression. We then investigated a regulatory role of FADD in T-acute lymphoblastic leukemia (T-ALL) using Jurkat cells as a model. Jurkat cells stably depleted of FADD (FADD Jurkat) expression exhibited dampened proliferation, hypersensitivity to Etoposide-induced intrinsic apoptosis whereas near total resistance to TRAIL-induced extrinsic apoptosis. Comparison between wild type and FADD Jurkat cells using iTRAQ-based proteomics revealed considerably altered expression spectrum of genes, and led us to focus on metabolic pathways. Investigation of glycolytic and mitochondrial pathways and relevant enzymes revealed that FADD knockout triggered a metabolic shift from glycolysis to mitochondrial respiration in Jurkat cells. Re-expression of FADD in FADD Jurkat cells partially rescued glycolytic capacity. FADD loss triggers global metabolic reprogramming in Jurkat cells and therefore remains as a potential druggable target for ALL treatment.

摘要

Fas 相关死亡结构域（FADD）长期以来一直被认为是细胞外凋亡途径中至关重要的衔接蛋白。尽管 FADD 的非凋亡功能逐渐被发现并得到证实，但它的相应生理和病理意义仍不清楚。基于 GWAS 目录和 GTEx 门户数据库，发现与白血病易感性相关的 17 个 SNP 与 FADD 表达有关。然后，我们使用 Jurkat 细胞作为模型，研究了 FADD 在 T-急性淋巴细胞白血病（T-ALL）中的调节作用。FADD 稳定耗竭的 Jurkat 细胞（FADD Jurkat）表现出增殖减弱、对依托泊苷诱导的内在凋亡敏感，而对 TRAIL 诱导的外在凋亡几乎完全耐药。使用 iTRAQ 基于蛋白质组学的野生型和 FADD Jurkat 细胞之间的比较揭示了基因表达谱的显著改变，使我们专注于代谢途径。对糖酵解和线粒体途径及相关酶的研究表明，FADD 敲除触发 Jurkat 细胞从糖酵解向线粒体呼吸的代谢转变。在 FADD Jurkat 细胞中重新表达 FADD 部分挽救了糖酵解能力。FADD 缺失在 Jurkat 细胞中引发了全局代谢重编程，因此仍然是 ALL 治疗的潜在可靶向目标。

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