STING Acts as a Rheostat of the Unfolded Protein Response to Regulate Antigen Presentation during Inflammation

In addition to inflammation, a growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson’s disease (PD). We reported previously that, in inflammatory conditions, the PD-associated proteins PINK1 and Parkin negatively regulate the presentation of mitochondrial antigens on MHC-I molecules, a process referred to as MitAP (Mitochondrial Antigen Presentation). In vitro and in vivo evidence in mice indicated that over- activation of MitAP, in the absence of PINK1, led to cytotoxic CD8+ T cell activation with attack on dopaminergic neurons and severe motor impairments reversible by L-DOPA. The molecular mechanisms regulating MitAP are poorly understood. We show here that the TRAM/TRIF arm of Toll-like receptor 4 (TLR4) triggers MitAP through a non-canonical pathway involving TBK1 but not IRF3. The cGAS-STING pathway plays a key role in MitAP through a small cytoplasmic domain, enabling STING to act as a rheostat to control the unfolded protein response (UPR). In the absence of STING, the UPR triggered during the inflammatory response is amplified, leading to a translational attenuation inhibiting the expression of XBP1s, a transcription factor required for MitAP. STING also broadly regulates the repertoire of peptides displayed at the cell surface during inflammation, highlighting a potential role in immunosurveillance. These findings establish STING as a key regulator coordinating the innate and adaptive immune response in inflammatory conditions, identifying the cGAS-STING pathway and the UPR as potential targets for therapeutic intervention during PD.