Post-translational modifications (PTM) are biochemical reactions on proteins that physiologically take place in the cell. Also, CFTR can be modified with different PTMs, such as methylation/de-methylation, phosphorylation or ubiquitination. For CFTR, PTMs called “PTM-code”, correspond to the modifications needed for the maturation of CFTR-F508del.
To understand which of these PTM-codes were necessary for the recovery of the mutated CFTR-F508del function, the researchers modified one by one and then all together, the CFTR sites on which the PTM-codes occur. The CFTR-F508del gene was modified in the positions corresponding to the PTM-code and inserted in human bronchial epithelial cells (CFBE41o−) treated with VX-445 (elexacaftor) and VX-661 (tezacaftor). The consequences of these changes were subsequently observed on the cells in combination with treatment with correctors. The experiments led the researchers to hypothesize that the PTM-code is not required for the correction of CFTR-F508del, which is in fact restored by the correctors regardless of the mutations on the PTM-code. The researchers then identified 3 demethylases (enzymes involved in methylation, one of the post-translational modifications) whose expression reduction would favour the corrector-induced functional recovery of CFTR-F508del. In the extension of the project (FFC#7/2020) the mechanisms through which methylation regulates the maturation of CFTR-F508del will be investigated.

Pubblications

• Salvi M, Non-Histone Protein Methylation: Molecular Mechanisms and Physiopathological Relevance, Curr Protein Pept Sci, 2020;21(7):640-641