UV-induced degradation of securin is mediated by SKP1-CUL1-βTrCP E3 ubiquitin ligase

• Published in: Journal of cell science Vol. 121; no. 11; pp. 1825 - 1831
• Main Authors: Limón-Mortés, M. Cristina, Mora-Santos, Mar, Espina, Águeda, Pintor-Toro, José A, López-Román, Antonio, Tortolero, María, Romero, Francisco
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 01-06-2008
• Subjects: Amino Acid Motifs - physiology; Animals; beta-Transducin Repeat-Containing Proteins - metabolism; Cell Cycle - physiology; Cell Cycle - radiation effects; Cell Cycle Proteins - metabolism; Cell Nucleus - metabolism; Cell Nucleus - radiation effects; Cercopithecus aethiops; COS Cells; Cullin Proteins - metabolism; Cytoplasm - metabolism; Cytoplasm - radiation effects; Down-Regulation - physiology; Enzyme Inhibitors - pharmacology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HeLa Cells; Humans; Neoplasm Proteins - metabolism; Neoplasm Proteins - radiation effects; Primates; Proteasome Endopeptidase Complex - metabolism; Securin; SKP Cullin F-Box Protein Ligases - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - physiology; Ubiquitination - radiation effects; Ultraviolet Rays
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.020552

Securin is a chaperone protein with bifunctional properties. It binds to separase to inhibit premature sister chromatid separation until the onset of anaphase, and it also takes part in cell-cycle arrest after UV irradiation. At metaphase-to-anaphase transition, securin is targeted for proteasomal destruction by the anaphase-promoting complex or cyclosome (APC/C), allowing activation of separase. However, although securin is reported to undergo proteasome-dependent degradation after UV irradiation, the ubiquitin ligase responsible for securin ubiquitylation has not been well characterized. In this study, we show that UV radiation induced a marked reduction of securin in both the nucleus and cytoplasm. Moreover, we show that GSK-3β inhibitors prevent securin degradation, and that CUL1 and βTrCP are involved in this depletion. We also confirmed that SKP1-CUL1-βTrCP (SCFβTrCP) ubiquitylates securin in vivo, and identified a conserved and unconventional βTrCP recognition motif (DDAYPE) in the securin primary amino acid sequence of humans, nonhuman primates and rodents. Furthermore, downregulation of βTrCP caused an accumulation of securin in non-irradiated cells. We conclude that SCFβTrCP is the E3 ubiquitin ligase responsible for securin degradation after UV irradiation, and that it is involved in securin turnover in nonstressed cells.