A variety of diseases such as degenerative neuromuscular disorders, cardiometabolic dysfunctions and cancer have been associated with abnormal protein folding and protein complex assembly, often through dysfunction of a group of specialized factors termed molecular chaperones. Building a detailed understanding of the mechanisms by which molecular chaperones participate in the onset and the development of disease is important for the design of new diagnosis and therapeutic tools.

During the past decade, our laboratory has discovered many proteins that regulate the activity and function of molecular chaperones. We first identified a cell machinery involved in biogenesis of nuclear RNA polymerases (RNAP I, II, III). Some of the newly discovered factors, the RNA Polymerase II-Associated Proteins (RPAP), act as co-chaperones in RNAP assembly and nuclear import. More recently we discovered a novel family of lysine methyltransferases that preferentially target and regulate molecular chaperones. Indeed, the posttranslational modification of a chaperone, for example the simple addition of a methyl group on a specific residue of chaperones such as VCP and Hsp70, can modify its activity and function. This finding led us to propose the existence of a chaperone posttranslational modification code, that we termed the ‘‘chaperone code’’, which is at play to orchestrate the proper folding and assembly of protein complexes that make up the human proteome.

Our research couples state-of-the-art approaches of proteomics, biochemistry and molecular and cellular biology, in both cellular models and clinical samples, to build a better understanding of chaperone regulation in health and disease. Decrypting the chaperone code will help defining new strategies for reverting chaperone dysfunction or stimulating normal chaperone activity in disease conditions. Characterization of the chaperone code will also lead to the discovery of biomarkers for the diagnosis and prognosis of disease.

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