Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.
Cytokines affect a variety of cellular functions, including regulation of cell numbers by suppression of programmed cell death. Suppression of apoptosis requires receptor signalling through the activation of Janus kinases and the subsequent regulation of members of the B-cell lymphoma 2 (Bcl-2) family. Here we demonstrate that a Bcl-2-family-related protein, Hax1, is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of Hax1 with the mitochondrial proteases Parl (presenilin-associated, rhomboid-like) and HtrA2 (high-temperature-regulated A2, also known as Omi). These interactions allow Hax1 to present HtrA2 to Parl, and thereby facilitates the processing of HtrA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed HtrA2 prevents the accumulation of mitochondrial-outer-membrane-associated activated Bax, an event that initiates apoptosis. Together, the results identify a previously unknown sequence of interactions involving a Bcl-2-family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting.
Chao
Jyh-Rong
JR
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Parganas
Evan
E
Boyd
Kelli
K
Hong
Cheol Yi
CY
Opferman
Joseph T
JT
Ihle
James N
JN
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005804:Genes, Lethal; D000074923:High-Temperature Requirement A Serine Peptidase 2; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D045726:Metalloproteases / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C491295:Hs1bp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D051028:bcl-2-Associated X Protein; D045726:Metalloproteases; D012697:Serine Endopeptidases; C512710:PARL protein, mouse; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse