PKD2/polycystin-2 induces autophagy by forming a complex with BECN1

Abstract

Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca(2+)that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca(2+)with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2(D509V), a Ca(2+)channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca(2+)mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Comisión Nacional de Investigación y Desarrollo Tecnológico (CONICYT, Chile) Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT 1160820 1180495 1181361 1200490 1171075 Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) ACT172066 FONDAP 15130011 CONICYT PhD fellowships 21140458 21140848 21140671 CONICYT International Investigation Project PII20150073 PEW Latin American Fellows Program in the Biomedical Science 00002991 United States Department of Health & Human Services National Institutes of Health (NIH) - USA HL-120732 HL-128215 HL-126012 HL-147933 U-inicia Program at Universidad de Chile UI024/19 Houston Methodist Research Institute International Centre for Genetic Engineering and Biotechnology, ICGEB CRP/CHL16-0