On March 2, 2020, Professor Hui Zheng’s research team in Soochow University published a study entitled "Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling" in Nature Communications. The study identified a new substrate which is modified by linear ubiquitination. Importantly, this study revealed a key mechanism controlling interferon (IFN) antiviral signaling mediated by linear ubiquitination.
Current research on linear ubiquitination modifications mainly focuses on the field of NF-κB inflammation signaling. So far, a few linearly ubiquitinated substrates have been identified, including NEMO, IRF3, ASC and TRIM25. This study found that the transcription factor STAT1 has linear ubiquitination modifications in resting cells. Furthermore, a series of experiments demonstrated that STAT1 is a new linearly ubiquitinated substrate.
Recent advances have revealed three regulatory mechanisms for linear ubiquitination modification: (1) promoting the activation of signaling proteins; (2) promoting the recruitment of specific signaling proteins; (3) promoting the degradation of substrate proteins. This study revealed another regulatory mechanism for linear ubiquitination: linear ubiquitination inhibits the interaction between transcription factors and their upstream signals. The study showed that linear ubiquitination blocks the binding of STAT1 to IFNAR2, thereby inhibiting the phosphorylation and activation of STAT1 and maintaining homeostasis of intracellular IFN signaling. This intrinsic negative regulation of transcription factors is different from the inhibition of NF-κB. The transcription factor NF-κB has an intrinsic negative regulatory factor IκB protein in cells, and STAT1 has not found such an intrinsic negative regulatory protein. Linear ubiquitination negatively regulates the activation of transcription factors, which may provide new ideas for understanding how transcription factors maintain homeostasis in cells. This regulatory mechanism is also important for controlling the excessive activation of IFN and avoiding autoimmune diseases.
Given that STAT1 linear ubiquitination prevents STAT1 activation, how can self-secreted IFN or exogenously administered IFN activate STAT1 and mediate the transducation of IFN signaling pathways? Interestingly, the study found that IFN can use OTULIN to quickly remove the linear ubiquitination of STAT1, thereby promoting the effective activation of STAT1. These studies suggest that linear ubiquitination is similar to a lock for STAT1 signaling activation and that OTULTN is the key. IFN uses OTULIN to unlock linearly ubiquitinated STAT1, allowing STAT1 to be activated. This fine regulation provides an efficient means for the switch between the homeostasis and activation of STAT1 signaling.
Importantly, this study revealed that a variety of viral infections can significantly upregulate HOIP mRNA and protein levels, thereby increasing the linear ubiquitination modification of STAT1, and ultimately inhibiting the activation of IFN signal, which promotes viral infection. These findings reveal a new mechanism by which viruses use linear ubiquitination modifications to escape host IFN antiviral immune response. Based on the above findings, the study further used Rbck1+/- mice to confirm the regulation of linear ubiquitination modification on IFN antiviral signals. In summary, the study promotes a better understanding of how IFN activates signaling pathways and exerts antiviral effects, and provides a potential new target for improving the efficacy of clinical IFN antiviral therapy.
Yibo Zuo is the first author of the paper, and other authors include Qian Feng, Lincong Jin, Fan Huang, Ying Miao and so on. Professor Hui Zheng is the corresponding author of the paper.