Intracellular trafficking in innate immunity

点击翻译按钮获取中文摘要

Innate and cell intrinsic immune responses constitute a rapid defence system against incoming pathogens. While essential to survival, excessive activity of these responses is potentially detrimental to the host, with inborn genetic errors of these systems leading to disease. To prevent aberrant induction, while retaining effective anti-viral activity, innate immunity has to be tightly regulated. Intracellular trafficking has recently emerged as a central determinant of innate immune signalling, including in type I interferon (IFN) induction via DNA sensing, Toll-like receptor (TLR) activation and autophagy. We have identified mutations in three components of the endoplasmic reticulum (ER)-Golgi trafficking axis associated with phenotypes falling within the type I interferonopathy (T1I) spectrum i.e. monogenic diseases associated with enhanced type I IFN signalling. Currently, only limited treatment options are available for these devastating disorders, and the underlying molecular mechanisms are poorly understood. Our data indicate that COPA, ARF1 and ARFGEF1 are important for trafficking of a signalling adaptor central to DNA sensing i.e. STING. Mutations in COPA, causing COPA syndrome in humans, result in accumulation of STING at the ER-Golgi intermediate compartment (ERGIC) and chronic STING activation. Pathogenic mutations in ARF1 and ARFGEF1, causing novel T1Is, promote STING-dependent induction of type I IFN responses. Based on these preliminary data, our primary research aim is to define the precise relationship of COPA, ARF1, ARFGEF1 to each other and to STING, and thereby inform our understanding of ER-Golgi trafficking in innate immune signalling. In our first work package, we will define the mechanism of action of the novel mutations that we have identified in ARF1 and ARFGEF1, examining their impact on the localisation and activation of STING, and the consequences on downstream signalling and ARF1/ARFGEF1-dependent vesicular transport. In the second aim, we will explore the hierarchy of STING-COPA-ARF1-ARFGEF1, further dissect the mechanism(s) of STING recruitment to trafficking vesicles, and examine the mode of trafficking. As STING signalling is not the only innate immune pathway involving ER-Golgi trafficking, in a third aim, we will explore the impact of the COPA-ARF1-ARFGEF1 axis on TLR activity and autophagy. Taken together, our exploration of the molecular and cellular consequences of Mendelian disease-associated mutations will provide novel insights into the fundamental regulation of innate immunity by ER-Golgi trafficking, and characterise the key players involved. In this way, we will better understand how pathogenic, chronic immune activity is prevented, and thus inform the future treatment of both rare Mendelian disorders and more common disease states characterised by dysregulated innate immune responses.