Kemp Michael G, Lindsey-Boltz Laura A, Sancar Aziz
From the Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599
From the Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
J Biol Chem. 2015 May 8;290(19):12184-94. doi: 10.1074/jbc.M115.649301. Epub 2015 Mar 19.
The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders.
阳光中的紫外线（UV）波长引发或加剧自身免疫性疾病红斑狼疮症状的机制尚不清楚，但可能涉及固有免疫系统的作用。我们在此表明，紫外线辐射可增强角质形成细胞和其他人类细胞中，免疫信号转录因子干扰素调节因子3（IRF3）对胞质DNA和环二核苷酸的依赖于STING（干扰素基因刺激因子）的激活。此外，我们发现这种固有免疫反应的调节也发生在紫外线模拟化学致癌物作用下，且其方式独立于DNA修复以及几种DNA损伤和细胞应激反应信号通路。相反，我们发现紫外线对STING依赖的IRF3激活的刺激是由于凋亡信号依赖的ULK1（Unc51样激酶1）破坏，ULK1是一种负向调节STING的自噬蛋白。因此，紫外线诱导的DNA损伤导致的ULK1信号失调，可能是自身免疫性疾病患者暴露于阳光紫外线产生负面影响的原因。
