Submitted August 21, 2008
Accepted March 25, 2009
Naturally occurring short splice variant of CYLD positively regulates dendritic cell function
Cathy Cecilia Srokowski, Joumana Masri, Nadine Hovelmeyer, Anna Katharina Krembel, Christine Tertilt, Dennis Strand, Karsten Mahnke, Ramin Massoumi, Ari Waisman*, and Hansjorg Schild
Institute for Immunology, Johannes Gutenberg University, Mainz, Germany
First Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany
Department of Dermatology, University of Heidelberg, Heidelberg, Germany
Department of Laboratory Medicine, Clinical Research Center, Lund University, Malmo, Sweden
* Corresponding author; email: waisman{at}uni-mainz.de.
Deubiquitination of NF-
B members by CYLD is crucial in controlling the magnitude and nature of cell activation. The role of the naturally occurring CYLD splice variant in dendritic cell (DC) function was analyzed using CYLDex7/8 mice, which lack the full-length CYLD (flCYLD) transcript and overexpress the short splice variant (sCYLD). Bone marrow derived DCs from CYLDex7/8 mice display a hyperactive phenotype in vitro and in vivo and have a defect in establishing tolerance using DEC-205-mediated antigen targeting to resting DCs. The combination of sCYLD overexpression and lack of flCYLD in CYLDex7/8 DCs leads to enhanced NF-B activity accompanied by an increased nuclear translocation of the IB molecule Bcl-3, along with nuclear p50 and p65. This suggests that in contrast to flCYLD, sCYLD is a positive regulator of NF-B activity and its overexpression induces a hyperactive phenotype in DCs.
