In silico exploration of the RAPTOR-STAT3 interface reveals potential crosstalk between mTORC1 and JAK-STAT pathways in Sjogren's syndrome and its linked cancer.

The Sjogrensyndrome (SS) is a chronic autoimmune disease that primarily affects the salivary glands. It has been associated with increased cancer risk, which implies that carcinogenic and autoimmune pathways may be interacting. Although being an integral component of mTOR complex 1 (mTORC1), regulatory-associated protein of mTOR (RAPTOR) is crucial for linking mTOR immunesignaling to cellular metabolism. Signal transducer and activator of transcription 3(STAT3) is the link between cancer-related and inflammation pathways. In this study, we used an integrative computational biology analysis, whichfocuses on non-experimental-based evidence, to investigate the potential of STAT3-RAPTOR crosstalk in the pathophysiology of Sjogren's syndrome and its related cancer. Protein-protein interaction (PPI) networks constructed in STRING and analysed and confirmed in Cytoscape network topology parameters demonstrated that STAT3 and RAPTOR are important interacting nodes in immune-metabolic signaling networks. Protein-protein interface characterisation of STAT3 by PDBsum revealed significant contact interfaces between the protein and RAPTOR, and molecular docking that ClusPro was performed and confirmed by HADDOCK. UniProt, EMBL-EBI ProtVar, and AlphaMissense helped in determining the human missense variants of STAT3 and RAPTOR to determine the functional relevance. GEPIA shows that RAPTOR and STAT3 are co-expressed in cancer data sets in terms of transcriptomic co-expression study. Importantly, the simultaneous expression was found to be preserved in autoimmune target tissue through disease-specific validation of salivary gland transcriptome data of Sjogren syndrome patients (GSE23117) using Autoimmune Disease Explorer (ADEx). All these findings indicate that there exists a bidirectional interaction between STAT3 and RAPTOR as a common immunometabolic signaling pathway that connects Sjogren's disease to the molecular signaling that follows the malignancy. Future wet-laboratory experiments will be required to experimentally validate the predicted interactions and their functional implications.