title: Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival.
abstract: Transglutaminase 2 (TGase 2) promotes nuclear factor-κB (NF-κB) activity through depletion of the inhibitory subunit of NF-κB (I-κBα) via protein cross-linking, leading to resolution of inflammation. Increased expression of TGase 2 contributes to inflammatory disease pathogenesis via constitutive NF-κB activation. Conversely, TGase 2 inhibition often reverses inflammation in animal models. The role of TGase 2 in apoptosis remains less clear, as both pro- and anti-apoptotic functions of TGase 2 have been demonstrated under different experimental conditions. Apoptosis is intact in a TGase 2 knock out mouse (TGase2(-/-)), which is phenotypically normal. However, upon exposure to tumor necrosis factor (TNF)-α-induced apoptotic stress, mouse embryonic fibroblasts (MEFs) from TGase2(-/-) mice were more sensitive to cell death than MEFs from wild-type (TGase 2(+/+)) mice. In the current study, to explore the role of TGase 2 in apoptosis, TGase 2-binding proteins were identified by LC/MS. TGase 2 was found to associate with cathepsin D (CTSD). Binding of TGase 2 to CTSD resulted in the depletion of CTSD via cross-linking in vitro as well as in MEFs, leading to decreased levels of apoptosis. Furthermore, cytoplasmic CTSD levels were higher in MEFs from TGase 2(-/-) mice than in those from TGase 2(+/+) mice, as were caspase 3 activation and poly (ADP-ribose) polymerase (PARP) processes. These results suggest that TGase 2, while not previously implicated as a major regulatory factor in apoptosis, may regulate the balance between cell survival and cell death through the modulation of CTSD levels.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Republic of Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Eu-Ree
authors.initials: ER
authors.lastname: Ahn
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.forename: Soo-Youl
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002402:Cathepsin D / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D003513:Cycloheximide / Q000494:pharmacology; D004800:Enzymes, Immobilized; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D053719:Tandem Mass Spectrometry; D011503:Transglutaminases / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000302:isolation & purification
chemical_list: C494827:Bax protein, mouse; D004800:Enzymes, Immobilized; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D003513:Cycloheximide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D019204:GTP-Binding Proteins