Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5.
Regulated intramembrane proteolysis is a widely conserved mechanism for controlling diverse biological processes. Considering that proteolysis is irreversible, it must be precisely regulated in a context-dependent manner. Here, we show that phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is cleaved in its N-terminal transmembrane domain in response to mitochondrial membrane potential (ΔΨ(m)) loss. This ΔΨ(m) loss-dependent cleavage of PGAM5 was mediated by presenilin-associated rhomboid-like (PARL). PARL is a mitochondrial resident rhomboid serine protease and has recently been reported to mediate the cleavage of PINK1, a mitochondrial Ser/Thr protein kinase, in healthy mitochondria with intact ΔΨ(m). Intriguingly, we found that PARL dissociated from PINK1 and reciprocally associated with PGAM5 in response to ΔΨ(m) loss. These results suggest that PARL mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria. Our data provide a prototypical example of stress-dependent regulation of PARL-mediated regulated intramembrane proteolysis.
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
Shiori
S
Sekine
Yusuke
Y
Kanamaru
Masato
M
Koike
Ayako
A
Nishihara
Masahiro
M
Okada
Hideyuki
H
Kinoshita
Miki
M
Kamiyama
Junichi
J
Maruyama
Yasuo
Y
Uchiyama
Naotada
N
Ishihara
Kohsuke
K
Takeda
Hidenori
H
Ichijo
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D000099202:PTEN-Induced Putative Kinase
D002352:Carrier Proteins; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C529563:PGAM5 protein, human; C485223:PARL protein, human