Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice.
The giant cytosolic protease tripeptidyl peptidase II (TPPII) has been implicated in the regulation of proliferation and survival of malignant cells, particularly lymphoma cells. To address its functions in normal cellular and systemic physiology we have generated TPPII-deficient mice. TPPII deficiency activates cell type-specific death programs, including proliferative apoptosis in several T lineage subsets and premature cellular senescence in fibroblasts and CD8(+) T cells. This coincides with up-regulation of p53 and dysregulation of NF-kappaB. Prominent degenerative alterations at the organismic level were a decreased lifespan and symptoms characteristic of immunohematopoietic senescence. These symptoms include accelerated thymic involution, lymphopenia, impaired proliferative T cell responses, extramedullary hematopoiesis, and inflammation. Thus, TPPII is important for maintaining normal cellular and systemic physiology, which may be relevant for potential therapeutic applications of TPPII inhibitors.
Huai
Jisen
J
Clinic for Radiotherapy and Department of Experimental Anaesthesiology, University Hospital Freiburg, 79106 Freiburg, Germany.
Firat
Elke
E
Nil
Ahmed
A
Million
Daniele
D
Gaedicke
Simone
S
Kanzler
Benoit
B
Freudenberg
Marina
M
van Endert
Peter
P
Kohler
Gabriele
G
Pahl
Heike L
HL
Aichele
Peter
P
Eichmann
Klaus
K
Niedermann
Gabriele
G
D000375:Aging / Q000276:immunology*; D000626:Aminopeptidases; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005347:Fibroblasts; D017353:Gene Deletion; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases