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Covalent NEDD8 conjugation increases RCAN1 protein stability and potentiates its inhibitory action on calcineurin

Eun Hye Noh1, Hee Sook Hwang, Hee Sun Hwang

  • 1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.

Plos One
|November 3, 2012
PubMed

Insights

Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) modifies Regulator of calcineurin 1 (RCAN1), enhancing its stability and calcineurin binding. This neddylation process inhibits RCAN1 proteasomal degradation, impacting NFAT signaling.

Area of Science:

  • Cellular and Molecular Biology
  • Protein Modification and Signaling
  • Ubiquitin-like Modifier Biology

Background:

  • Regulatory roles of NEDD8 (neural precursor cell-expressed developmentally down-regulated 8) are emerging in cellular processes.
  • NEDD8 targets and their functional impacts remain largely uncharacterized.
  • Regulator of calcineurin 1 (RCAN1) inhibits calcineurin signaling and is targeted for proteasomal degradation via ubiquitination.

Purpose of the Study:

  • To investigate the neddylation of RCAN1 and its functional consequences.
  • To elucidate the regulatory mechanism of RCAN1 stability and activity by NEDD8.

Main Methods:

  • Identifying lysine residues on RCAN1 (RCAN1-1S) targeted for NEDD8 conjugation.
  • Assessing the effect of neddylation on RCAN1 protein stability and cellular localization.
  • Evaluating the impact of neddylation on RCAN1 interaction with calcineurin and downstream signaling.

Main Results:

  • NEDD8 is conjugated to RCAN1 at lysine residues K96, K104, and K107.
  • Neddylation enhances RCAN1 protein stability by inhibiting its proteasomal degradation.
  • Neddylation increases RCAN1 binding to calcineurin, potentiating its inhibitory effect on NFAT signaling.

Conclusions:

  • This study reveals a novel regulatory mechanism for RCAN1 function through NEDD8 conjugation (neddylation).
  • Neddylation stabilizes RCAN1, enhances its inhibitory activity on calcineurin-NFAT signaling, and impacts cellular physiology.

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