Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation.
Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation.
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DOI：
10.1038/srep31159
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发表时间：
2016-08-08
影响因子：
4.6
通讯作者：
Arthur JS
中科院分区：
文献类型：
--
作者：
McGuire VA;Ruiz-Zorrilla Diez T;Emmerich CH;Strickson S;Ritorto MS;Sutavani RV;Weiβ A;Houslay KF;Knebel A;Meakin PJ;Phair IR;Ashford ML;Trost M;Arthur JS
富马酸二甲酯(DMF)具有抗炎特性，已被批准用于治疗牛皮癣和多发性硬化症。虽然在临床上有效，但它的分子靶点仍然难以捉摸--尽管已知它能激活抗氧化途径。我们发现，DMF抑制促炎细胞因子的产生，对TLR激动剂的反应不依赖于Nrf2-Keap1抗氧化途径。相反，我们发现DMF在体外和细胞内都可以抑制参与K63和M1多泛素链形成的E2结合酶。K63和M1链的形成是将TLR激活与下游信号联系起来所必需的，与K63和/或M1链形成中的阻断一致，DMF抑制NFκB和ERK1/2的激活，导致致炎细胞因子的丧失。总之，这些结果揭示了DMF的一个新的分子靶点，并表明一种临床批准的药物可以抑制TLR诱导的信号复合体中M1和K63链的形成。因此，选择性靶向E2可能是一种可行的自身免疫策略。
Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.