Mono-ubiquitination drives nuclear export of the human DCN1-like protein hDCNL1 |
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Authors: | Wu Kenneth Yan Hua Fang Lei Wang Xinjiang Pfleger Cathie Jiang Xuejun Huang Lan Pan Zhen-Qiang |
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Institution: | Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, New York 10029-6574, USA. |
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Abstract: | Conjugation of Nedd8 to a cullin protein, termed neddylation, is an evolutionarily conserved process that functions to activate the cullin-RING family E3 ubiquitin ligases, leading to increased proteasomal degradation of a wide range of substrate proteins. Recent emerging evidence demonstrates that cellular neddylation requires the action of Dcn1, which, in humans, consists of five homologues designated as hDCNL1-5. Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system. In addition, the hDCNL1 N-terminal ubiquitin-binding domain is necessary and sufficient to mediate mono-ubiquitination. Finally, fluorescence microscopic and subcellular fractionation analyses revealed a role for mono-ubiquitination in driving nuclear export of hDCNL1. Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1, thereby regulating hDCNL1-dependent activation of the cullin-RING E3 ubiquitin ligases in selected cellular compartments. |
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Keywords: | Cell Compartmentation Post-translational Modification Protein Translocation Ubiquitin Ligase Ubiquitination Dcn1 cullin-RING E3 |
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