| 1. |
- Bros, Matthias, et al.
(författare)
-
Mutated cylindromatosis gene affects the functional state of dendritic cells
- 2010
-
Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 40:10, s. 2848-2857
-
Tidskriftsartikel (refereegranskat)abstract
- Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappa B signaling pathway and attenuates NF-kappa B and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLDex7/8), display a higher content of nuclear RelB and express elevated levels of NF-kappa B family members as well as of known NF-kappa B-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLDex7/8 DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLDex7/8 DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-kappa B and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLDex7/8 DC and re-established their tolerogenic function. DC derived from CYLD knockout mice showed no functional alterations compared with WT DC. Therefore, although complete loss of CYLD may be compensated for by other endogenous NF-kappa B inhibitors, CYLDex7/8 acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-kappa B activity may result in disturbed maintenance of peripheral tolerance.
|
|
| 2. |
- Shimokawa, Noriaki, et al.
(författare)
-
CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
- 2010
-
Ingår i: EMBO Journal. - : European Molecular Biology Organization. - 0261-4189 .- 1460-2075. ; 29:14, s. 2421-2432
-
Tidskriftsartikel (refereegranskat)abstract
- Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85(Deltaex2)) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85(Deltaex2) animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85(Deltaex2) mice.
|
|
