title: Covalent NEDD8 conjugation increases RCAN1 protein stability and potentiates its inhibitory action on calcineurin.
abstract: Similar to ubiquitin, regulatory roles for NEDD8 (neural precursor cell-expressed developmentally down-regulated 8) are being clarified during cell growth, signal transduction, immune response, and development. However, NEDD8 targets and their functional alterations are not well known. Regulator of calcineurin 1 (RCAN1/DSCR1P1) is located near the Down syndrome critical region on the distal part of chromosome 21, and its gene product is an endogenous inhibitor of calcineurin signaling. RCAN1 is modified by ubiquitin and consequently undergoes proteasomal degradation. Here we report that NEDD8 is conjugated to RCAN1 (RCAN1-1S) via three lysine residues, K96, K104, and K107. Neddylation enhances RCAN1 protein stability without affecting its cellular location. In addition, we found that neddylation significantly inhibits proteasomal degradation of RCAN1, which may underlie the ability of NEDD8 to enhance RCAN1 stability. Furthermore, neddylation increases RCAN1 binding to calcineurin, which potentiates its inhibitory activity toward downstream NFAT signaling. The present study provides a new regulatory mechanism of RCAN1 function and highlights an important role for diverse RCAN1-involved cellular physiology.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Noh
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Hwang
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Hwang
authors.forename: Boram
authors.initials: B
authors.lastname: Min
authors.forename: Eunju
authors.initials: E
authors.lastname: Im
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D000075687:NEDD8 Protein; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D050778:NFATC Transcription Factors; C108612:RCAN1 protein, human; D014452:Ubiquitins; D019703:Calcineurin