The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity.
Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid beta-precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ domain. We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and beta-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins.
Gupta
Sanjeev
S
Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Singh
Rajesh
R
Datta
Pinaki
P
Zhang
Zhijia
Z
Orr
Christopher
C
Lu
Zhixian
Z
Dubois
Garrett
G
Zervos
Antonis S
AS
Meisler
Miriam H
MH
Srinivasula
Srinivasa M
SM
Fernandes-Alnemri
Teresa
T
Alnemri
Emad S
ES
D000595:Amino Acid Sequence; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D053764:Presenilin-1; D053766:Presenilin-2; D012697:Serine Endopeptidases / Q000378:metabolism*
D001426:Bacterial Proteins; C066496:DegS protein, Bacteria; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2