PMID- 20644164
OWN - NLM
STAT- MEDLINE
DCOM- 20100922
LR  - 20201209
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 185
IP  - 4
DP  - 2010 Aug 15
TI  - Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs 
      positive selection in a NF-kappaB essential modulator-dependent manner.
PG  - 2032-43
LID - 10.4049/jimmunol.0903919 [doi]
AB  - The cylindromatosis tumor suppressor gene (Cyld) encodes a deubiquitinating 
      enzyme (CYLD) with immunoregulatory function. In this study, we evaluated the 
      role of Cyld in T cell ontogeny by generating a mouse (Cyld(Delta9)) with a 
      thymocyte-restricted Cyld mutation that causes a C-terminal truncation of the 
      protein and reciprocates catalytically inactive human mutations. Mutant mice had 
      dramatically reduced single positive thymocytes and a substantial loss of 
      peripheral T cells. The analyses of polyclonal and TCR-restricted thymocyte 
      populations possessing the mutation revealed a significant block in positive 
      selection and an increased occurrence of apoptosis at the double-positive stage. 
      Interestingly, in the context of MHC class I and II restricted TCR transgenes, 
      lack of functional CYLD caused massive deletion of thymocytes that would have 
      been positively selected, which is consistent with an impairment of positive 
      selection. Biochemical analysis revealed that Cyld(Delta9) thymocytes exhibit 
      abnormally elevated basal activity of NF-kappaB and JNK. Most importantly, 
      inactivation of NF-kappaB essential modulator fully restored the NF-kappaB 
      activity of Cyld(Delta9) thymocytes to physiologic levels and rescued their 
      developmental and survival defect. This study identifies a fundamental role for 
      functional CYLD in establishing the proper threshold of activation for thymocyte 
      selection by a mechanism dependent on NF-kappaB essential modulator.
FAU - Tsagaratou, Ageliki
AU  - Tsagaratou A
AD  - School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
FAU - Trompouki, Eirini
AU  - Trompouki E
FAU - Grammenoudi, Sofia
AU  - Grammenoudi S
FAU - Kontoyiannis, Dimitris L
AU  - Kontoyiannis DL
FAU - Mosialos, George
AU  - Mosialos G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100719
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NEMO protein, mouse)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.19.12 (CYLD protein, mouse)
RN  - EC 3.4.19.12 (Deubiquitinating Enzyme CYLD)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
SB  - IM
MH  - Animals
MH  - Binding Sites/genetics
MH  - CD4-Positive T-Lymphocytes/cytology/immunology/metabolism
MH  - CD8-Positive T-Lymphocytes/cytology/immunology/metabolism
MH  - Cysteine Endopeptidases/genetics/*metabolism
MH  - Deubiquitinating Enzyme CYLD
MH  - Female
MH  - Flow Cytometry
MH  - Immunoblotting
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred Strains
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Mutation
MH  - NF-kappa B/*metabolism
MH  - Receptors, Antigen, T-Cell/genetics/immunology/metabolism
MH  - Thymus Gland/cytology/*immunology/*metabolism
MH  - Ubiquitination
EDAT- 2010/07/21 06:00
MHDA- 2010/09/24 06:00
CRDT- 2010/07/21 06:00
PHST- 2010/07/21 06:00 [entrez]
PHST- 2010/07/21 06:00 [pubmed]
PHST- 2010/09/24 06:00 [medline]
AID - jimmunol.0903919 [pii]
AID - 10.4049/jimmunol.0903919 [doi]
PST - ppublish
SO  - J Immunol. 2010 Aug 15;185(4):2032-43. doi: 10.4049/jimmunol.0903919. Epub 2010 
      Jul 19.