PARP7 as a New Negative Feedback Regulator of Type I Interferon Signaling

Type I interferons (IFNs) are signaling molecules involved in the antiviral response. A high level of type I IFNs is one of the most common characteristics of systemic lupus erythematosus (SLE). Type I IFNs induce, or turn on, about 500 genes, most of which encode molecules that help us fight viruses. A very small subset of genes induced by type I IFNs encode negative regulators, which act as built-in dimmers of the IFN response to minimize tissue damage. Dr. Yan recently found that one of these IFN dimmers, PARP7, inhibits IFN induction, targeting many immune pathways that activate type I IFNs. Targeting the early steps of the IFN pathway has profound potential for lupus treatment. However, the function of PARP7 and how it inhibits IFN induction has not been explored. Dr. Yan will investigate how PARP7 blocks IFN induction and whether this “built-in dimming” trait can be harnessed to treat lupus.

Dr. Yan will first explore how PARP7 inhibits type I IFN induction. He will determine what molecules PARP7 interacts with and where it goes within cells during IFN activation. Dr. Yan will compare cells from healthy people to those from people with SLE to test whether PARP7 is higher in SLE and whether the levels of PARP7 correlate with disease severity. Lastly, Dr. Yan will use genetic tools to remove PARP7 in mice to determine whether the loss of PARP7 causes autoimmunity. To test its therapeutic potential, Dr. Yan will increase PARP7 production in multiple mouse models of lupus and assess whether disease symptoms improve.

What this study means for people with lupus

High interferon levels are among the most common signatures in people with lupus. New ideas are needed to control this pathway effectively. Multiple drugs that increase PARP7 are already available or in development, which means that findings from this study could be quickly translated into the clinic to improve the lives of people with lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Despite its heterogeneity, elevated type I interferon (IFN-I) signaling is one of the most common immunological signatures of SLE. IFN-I induces hundreds of genes (ISG), of which a small number of genes function as negative regulators to avoid overt activation of immune signaling. Deficiency of these genes in humans leads to severe autoimmune diseases, highlighting the importance of negative feedback ISGs in maintaining immune homeostasis. In preliminary data, we recently discovered PARP7 as a new negative feedback regulator of IFN-I induction. PARP7 inhibits multiple innate immune signaling pathways at the step of IRF3 and this inhibition requires PARP7 enzymatic activity to catalyze mono-ADP ribosylation. Further, Parp7 knockout and enzyme-dead mutant mice develop spontaneous and systemic autoimmunity with unique characteristics in the lung. Based on these findings, we hypothesize that PARP7 is a broad-acting negative feedback regulator of IFNI induction which can be harnessed to treat autoimmune diseases such as lupus. Targeting IFN-I “induction” in producing cells rather than “signaling” in recipient cells should be more effective as therapeutics. In Aim 1, we will elucidate the molecular mechanism by which PARP7 inhibits IFN-I induction in healthy and lupus cells. We will investigate PARP7 interaction with IRF3, ADP-ribosylation, and subcellular localization. We will also analyze PARP7 expression and activity in type I interferonopathy and SLE patient cells. In Aim 2, we will determine the physiological functions of PARP7 in tissue homeostasis and lupus pathogenesis in mice. We will characterize the autoimmune phenotypes of Parp7-KO and Parp7-H532A mice. We will also modulate PARP7 expression or activity in lupus mouse models either genetically or with existing small molecule agonists and antagonists. Together, we hope to elucidate PARP7 mechanism in IFN-I signaling and harness this “built-in dimming” mechanism of IFN-I induction as potential treatments for lupus.