Figure 3.

Mechanisms of HO-1 dysregulation in cystic fibrosis (CF). In the absence of functional CFTR: (A) MΦs have a blunted PI3K/AKT signaling in response to TLR4 activation, which leads to accumulation of miR-199a-5p, which reduces Cav1 expression. Loss of Cav1 impairs translocation and compartmentalization of HO-1 at the plasma membrane (PM); (B) blunted PI3K/AKT signaling in CF cells results in elevated levels of active GSK3β, which leads to Nrf2 ubiquitination and proteasomal degradation and (C) affects the stability of HIF-1α. (D) NF-kB in CF cells competes for the Nrf2 co-activator CBP/p300, thus preventing Nrf2 transcriptional activity.