Divergent signaling via SUMO modification: potential for CFTR modulation

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is generally responsible for the cAMP/PKA regulated anion conductance at the apical membranes of secretory epithelial cells. Mutations in CFTR underlie cystic fibrosis (CF), in which the most common variant, F508del, causes protein misfolding and its proteasome-mediated degradation. A new pathway that contributes to mutant CFTR degradation is mediated by the small heat shock protein, Hsp27, which cooperates with Ubc9, the E2 enzyme for SUMOylation, to selectively conjugate mutant CFTR with SUMO-2/3. This SUMO paralog can form polychains, which are recognized by the ubiquitin E3 enzyme, RNF4, leading to CFTR ubiquitylation and recognition by the proteasome. We found also that F508del CFTR could be modified by SUMO-1, a paralog that does not support SUMO polychain formation. The use of different SUMO paralogs to modify and target a single substrate for divergent purposes is not uncommon. In this short review we discuss the possibility that conjugation with SUMO-1 could protect mutant CFTR from disposal by RNF4 and similar ubiquitin ligases. We hypothesize that such a pathway could contribute to therapeutic efforts to stabilize immature mutant CFTR and thereby enhance the action of therapeutics that correct CFTR trafficking to the apical membranes.

Keywords: SIM (SUMO-interacting motif); SUMO ligase; SUMO-specific peptidase; Ubc9 (SUMO-conjugating enzyme), multi-SUMOylation.

Fig. 1.

CFTR has three consensus sites for SUMOylation, ψKXE/D, followed by an acidic cluster. A schematic representation of their positions is shown.

Fig. 2.

F508del CFTR can be conjugated to both SUMO-1 as well as SUMO-2/3, whereas Hsp27 promotes selective SUMOylation of F508del CFTR by SUMO-2/3. HEK 293 cells were transfected with F508del CFTR and empty vector or Hsp27 DNAs as previoulsy described (1). Modification of F508del CFTR by endogenous SUMO paralogs was assessed by CFTR immunoprecipitation (IP) followed by SUMO-1 or SUMO-2/3 immunoblotting. An irrelevant IgG served as a control. SUMO density values were normalized to CFTR levels in the IPs and mean values from six experiments are provided in the bottom panel. [From Ahner et al. (1). Reprinted with permission.]