Figure 2.

TG2-mediated inhibition of autophagy in CF epithelial cells. Defective CFTR-mediated TG2 activation leads to BECN1 crosslinking and displaces BECN1 interactome away from the endoplasmic reticulum (ER). This mislocalization inhibits autophagosome formation, disables autophagy, and induces accumulation of SQSTM1 (p62). SQSTM1 accumulation leads to proteasome overload and favors sequestration of cross-linked TG2 substrates (PPARγ, IκBα, BECN1) within HDAC6⁺ aggresomes. The combined inhibition of protein and aggresome turnover may also favor the accumulation of F508del-CFTR (together with SQSTM1) within HDAC6⁺/ubiquitin⁺ intracellular aggregates. Defective autophagy inhibits the clearance of damaged mitochondria that contribute to the generation of pro-inflammatory ROS.