Wiesauer Ivana, Gaumannmüller Clemens, Steinparzer Iris, Strobl Birgit, Kovarik Pavel
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Mol Cell Biol. 2015 Feb;35(4):716-27. doi: 10.1128/MCB.01097-14. Epub 2014 Dec 15.
Interferons regulate immunity by inducing DNA binding of the transcription factor STAT1 through Y701 phosphorylation. Transcription by STAT1 needs to be restricted to minimize the adverse effects of prolonged immune responses. It remains unclear how STAT1 inactivation is regulated such that the transcription output is adequate. Here we show that efficient STAT1 inactivation in macrophages is coupled with processive transcription. Ongoing transcription feeds back to reduce the promoter occupancy of STAT1 and, consequently, the transcriptional output. Once released from the promoter, STAT1 is ultimately inactivated by Y701 dephosphorylation. We observe similar regulation for STAT2 and STAT3, suggesting a conserved inactivation mechanism among STATs. These findings reveal that STAT1 promoter occupancy in macrophages is regulated such that it decreases only after initiation of the transcription cycle. This feedback control ensures the fidelity of cytokine responses and provides options for pharmacological intervention.
干扰素通过诱导转录因子STAT1的Y701磷酸化从而使其与DNA结合来调节免疫。STAT1的转录需要受到限制，以尽量减少延长免疫反应的不利影响。目前尚不清楚STAT1失活是如何被调节的，以便转录输出量充足。在这里，我们表明巨噬细胞中高效的STAT1失活与持续转录相关。正在进行的转录会产生反馈，以减少STAT1对启动子的占据，从而减少转录输出量。一旦从启动子上释放，STAT1最终会通过Y701去磷酸化而失活。我们观察到STAT2和STAT3也有类似的调节，这表明STAT家族成员之间存在保守的失活机制。这些发现揭示，巨噬细胞中STAT1对启动子的占据是受到调节的，使得它仅在转录周期开始后才会减少。这种反馈控制确保了细胞因子反应的保真度，并为药物干预提供了选择。
