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: Se-Jin Kim, Kyung-Hee Kim, Eu-Ree Ahn, Byong Chul Yoo, Soo-Youl Kim
• Journal: Amino acids (Amino Acids) Vol. 44 Issue 1 Pg. 73-80 (Jan 2013) ISSN: 1438-2199 [Electronic] Austria
• PMID: 21960143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bax protein, mouse
• Enzymes, Immobilized
• Tumor Necrosis Factor-alpha
• bcl-2-Associated X Protein
• Cycloheximide
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Casp3 protein, mouse
• Caspase 3
• Cathepsin D
• Ctsd protein, mouse
• GTP-Binding Proteins

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cathepsin D (chemistry, isolation & purification, metabolism)
• Cell Survival
• Cells, Cultured
• Chromatography, Affinity
• Cycloheximide (pharmacology)
• Enzymes, Immobilized
• GTP-Binding Proteins (chemistry, metabolism)
• Gene Knockout Techniques
• Guinea Pigs
• Humans
• Mice
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Binding
• Protein Glutamine gamma Glutamyltransferase 2
• Protein Interaction Mapping
• Protein Multimerization
• Tandem Mass Spectrometry
• Transglutaminases (chemistry, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• bcl-2-Associated X Protein (chemistry, isolation & purification)