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LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
Output Details
Description
While the contribution of inflammation in the pathological process leading to
Parkinson’s disease (PD) is well established, a growing body of evidence supports a role for the long-lasting adaptive immune system in the disease. We have shown that in the absence of PINK1, over-activation of MitAP (Mitochondrial Antigen Presentation) in antigen presenting cells (APCs) engages autoimmune mechanisms leading to the establishment of cytotoxic CD8+ T cells. In the present study, we used a pharmacological and genetic approach to characterize the MitAP pathway at the molecular level. We showed that this antigen presentation pathway is induced in APCs in response to inflammatory signals through the sequential activation of TLR4, cGAS-STINGand the Unfolded Protein Response (UPR). A “UPR motif” present on a STING cytoplasmic domain was shown to specifically activate the UPR sensor IRE1. Remarkably, the PD-related protein LRRK2, acted with STING upstream of the UPR to regulate the transition from innate to adaptive immunity, thereby identifying this PD-related protein as a key player in the immune response during inflammation.
Identifier (DOI)
10.1101/2023.06.14.545012