Thioredoxin Regulates Adipogenesis through Thioredoxin-interacting Protein (Txnip) Protein Stability
Thioredoxin Regulates Adipogenesis through Thioredoxin-interacting Protein (Txnip) Protein Stability
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DOI：
10.1074/jbc.m111.267666
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发表时间：
2011-08-19
影响因子：
4.8
通讯作者：
Lee, Richard T.
中科院分区：
文献类型：
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作者：
Chutkow, William A.;Lee, Richard T.
Txnip（硫氧还蛋白相互作用蛋白）是体内代谢和脂肪形成的关键介质。据信Txnip的作用机制至少部分地通过抑制硫氧还蛋白的氧化还原信号传导功能来起作用。我们在这里测试了Txnip是否通过抑制硫氧还蛋白来抑制脂肪形成，并发现了作用的逆转; Txnip直接抑制脂肪形成，硫氧还蛋白结合通过增强Txnip蛋白的稳定性来调节Txnip。与Txnip不同，不能结合硫氧还蛋白（C247 S）的Txnip突变体不能阻止脂肪细胞分化，但通过蛋白酶体靶向更快地降解。发现内源性Txnip蛋白在脂肪形成开始时也快速降解，表明Txnip降解是脂肪细胞分化所需的。硫氧还蛋白过表达稳定Txnip蛋白水平以抑制脂肪形成，并且脂肪形成刺激物如胰岛素促进Txnip-硫氧还蛋白解离成更不稳定的游离Txnip状态。作为α-抑制蛋白，Txnip具有两个C-末端尾PPXY基序，其介导E3泛素连接酶结合和Txnip蛋白稳定性。突变的PPXY基序防止Txnip降解，即使当硫氧还蛋白结合丢失，并恢复C247 S Txnip抑制脂肪形成的能力。这些研究通过显示硫氧还蛋白通过蛋白质稳定化调节Txnip作为脂肪生成抑制剂的内在功能，提出了对Txnip-硫氧还蛋白信号传导的新的重新思考。
Txnip (thioredoxin-interacting protein) is a critical mediator of metabolism and adipogenesis in vivo. The mechanisms of action of Txnip are believed to operate at least in part by inhibiting the redox signaling functions of thioredoxin. We tested here whether Txnip suppressed adipogenesis by inhibiting thioredoxin and discovered a reversal of roles; Txnip inhibits adipogenesis directly, and thioredoxin binding regulates Txnip by enhancing Txnip protein stability. Unlike Txnip, a Txnip mutant that cannot bind thioredoxin (C247S) did not prevent adipocyte differentiation, but was degraded more quickly by proteasomal targeting. Finding that endogenous Txnip protein is also rapidly degraded at the onset of adipogenesis suggested that Txnip degradation is required for adipocyte differentiation. Thioredoxin overexpression stabilized Txnip protein levels to inhibit adipogenesis, and adipogenic stimulants such as insulin promoted Txnip-thioredoxin dissociation to the more labile free Txnip state. As an alpha-arrestin protein, Txnip has two C-terminal tail PPXY motifs that mediate E3 ubiquitin ligase binding and Txnip protein stability. Mutating the PPXY motifs prevented Txnip degradation, even when thioredoxin binding was lost, and restored the ability of C247S Txnip to inhibit adipogenesis. These studies present a novel reconsideration of Txnip-thioredoxin signaling by showing that thioredoxin regulates the intrinsic function of Txnip as an inhibitor of adipogenesis through protein stabilization.