Therefore, in CF, increased intracellular levels of ROS, induced by defective CFTR function, lead to the upregulation of the SUMO E3-ligase PIASy, which facilitates TG2 SUMOylation, persistent high TG2 protein levels, and sustained TG2 activation as the result of “permissive” elevated Ca2+ levels. Here, PIAS4 is linked to cystic fibrosis.