The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy.
Mutations in the PINK1 gene cause autosomal recessive Parkinson's disease. The PINK1 gene encodes a protein kinase that is mitochondrially cleaved to generate two mature isoforms. In addition to its protective role against mitochondrial dysfunction and apoptosis, PINK1 is also known to regulate mitochondrial dynamics acting upstream of the PD-related protein Parkin. Recent data showed that mitochondrial Parkin promotes the autophagic degradation of dysfunctional mitochondria, and that stable PINK1 silencing may have an indirect role in mitophagy activation. Here we report a new interaction between PINK1 and Beclin1, a key pro-autophagic protein already implicated in the pathogenesis of Alzheimer's and Huntington's diseases. Both PINK1 N- and C-terminal are required for the interaction, suggesting that full-length PINK1, and not its cleaved isoforms, interacts with Beclin1. We also demonstrate that PINK1 significantly enhances basal and starvation-induced autophagy, which is reduced by knocking down Beclin1 expression or by inhibiting the Beclin1 partner Vps34. A mutant, PINK1(W437X), interaction of which with Beclin1 is largely impaired, lacks the ability to enhance autophagy, whereas this is not observed for PINK1(G309D), a mutant with defective kinase activity but unaltered ability to bind Beclin1. These findings identify a new function of PINK1 and further strengthen the link between autophagy and proteins implicated in the neurodegenerative process.
Michiorri
S
S
Casa Sollievo della Sofferenza Hospital, CSS-Mendel Institute, Rome, Italy.
Gelmetti
V
V
Giarda
E
E
Lombardi
F
F
Romano
F
F
Marongiu
R
R
Nerini-Molteni
S
S
Sale
P
P
Vago
R
R
Arena
G
G
Torosantucci
L
L
Cassina
L
L
Russo
M A
MA
Dallapiccola
B
B
Valente
E M
EM
Casari
G
G
D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000648:ultrastructure; D009154:Mutation; D011494:Protein Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D020798:Two-Hybrid System Techniques; D000099202:PTEN-Induced Putative Kinase
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C491997:BECN1 protein, human