Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription

Wepreviously established that besides its canonical function as E3-ubiquitin ligase, parkin also behaves as a transcriptional repressor of p53. Here we show that parkin differently modulates presenilin-1 and presenilin-2 expression and functions at transcriptional level. Thus, parkin enhances/reduces the protein expression, promoter activity and mRNA levels of presenilin-1 and presenilin-2, respectively, in cells and in vivo. This parkin-associated function is independent of its ubiquitin-ligase activity and remains unrelated to its capacity to repress p53. Accordingly, physical interaction of endogenous or overexpressed parkin with presenilins promoters is demonstrated by chromatin immunoprecipitation assays (ChIP). Furthermore, we identify a consensus sequence, the deletion of which abolishes parkin-dependent modulation of presenilins-1/2 and p53 promoter activities. Interestingly, electrophoretic mobility shift assays (EMSA) revealed a physical interaction between this consensus sequence and wild-type but not mutated parkin. Finally, we demonstrate that the RING1-IBR-RING2 domain of parkin harbors parkin's potential to modulate presenilins promoters. This transcriptional control impacts on presenilins-associated phenotypes, since parkin increases presenilin-1- associated g-secretase activity and reduces presenilin-2-linked caspase-3 activation. Overall, our data delineate a promoter responsive element targeted by parkin that drives differential regulation of presenilin-1 and presenilin-2 transcription with functional consequences for g-secretase activity and cell death.