The NEDD8 E3 Ligase DCNL5 is Phosphorylated by IKK Alpha During Toll-like Receptor Activation

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2018 Jun 30

PMID 29958295

Citations 3

Authors

Yann Thomas

Daniel C Scott

Yosua Adi Kristariyanto

Jesse Rinehart

Kristopher Clark

Philip Cohen

Thimo Kurz

Affiliations

Soon will be listed here.

Abstract

The activity of Cullin-RING ubiquitin E3 ligases (CRL) is regulated by NEDD8 modification. DCN-like proteins promote Cullin neddylation as scaffold-like E3s. One DCNL, DCNL5, is highly expressed in immune tissue. Here, we provide evidence that DCNL5 may be involved in innate immunity, as it is a direct substrate of the kinase IKKα during immune signalling. We find that upon activation of Toll-like receptors, DCNL5 gets rapidly and transiently phosphorylated on a specific N-terminal serine residue (S41). This phosphorylation event is specifically mediated by IKKα and not IKKβ. Our data for the first time provides evidence that DCNL proteins are post-translationally modified in an inducible manner. Our findings also provide the first example of a DCNL member as a kinase substrate in a signalling pathway, indicating that the activity of at least some DCNLs may be regulated.

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References

Liu B, Tahk S, Yee K, Fan G, Shuai K . The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science. 2010; 330(6003):521-5. PMC: 3043201. DOI: 10.1126/science.1193787. View

Fischer E, Scrima A, Bohm K, Matsumoto S, Lingaraju G, Faty M . The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell. 2011; 147(5):1024-39. DOI: 10.1016/j.cell.2011.10.035. View

Soucy T, Smith P, Milhollen M, Berger A, Gavin J, Adhikari S . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458(7239):732-6. DOI: 10.1038/nature07884. View

Shembade N, Pujari R, Harhaj N, Abbott D, Harhaj E . The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. Nat Immunol. 2011; 12(9):834-43. PMC: 3205447. DOI: 10.1038/ni.2066. View

Sun S . The noncanonical NF-κB pathway. Immunol Rev. 2012; 246(1):125-40. PMC: 3313452. DOI: 10.1111/j.1600-065X.2011.01088.x. View

Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X . Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282(5396):2085-8. DOI: 10.1126/science.282.5396.2085. View

Park H, Hohn M, Umehara T, Guo L, Osborne E, Benner J . Expanding the genetic code of Escherichia coli with phosphoserine. Science. 2011; 333(6046):1151-4. PMC: 5547737. DOI: 10.1126/science.1207203. View

Clark K, Nanda S, Cohen P . Molecular control of the NEMO family of ubiquitin-binding proteins. Nat Rev Mol Cell Biol. 2013; 14(10):673-85. DOI: 10.1038/nrm3644. View

Liu M, Lee D, Chen C, Yen C, Li L, Lee H . IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell. 2011; 45(2):171-84. PMC: 3268914. DOI: 10.1016/j.molcel.2011.11.018. View

10.

Zhu F, Xia X, Liu B, Shen J, Hu Y, Person M . IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Mol Cell. 2007; 27(2):214-227. DOI: 10.1016/j.molcel.2007.05.042. View

11.

Shembade N, Harhaj N, Liebl D, Harhaj E . Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. EMBO J. 2007; 26(17):3910-22. PMC: 1994124. DOI: 10.1038/sj.emboj.7601823. View

12.

Hjerpe R, Bett J, Keuss M, Solovyova A, McWilliams T, Johnson C . UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome. Cell. 2016; 166(4):935-949. PMC: 5003816. DOI: 10.1016/j.cell.2016.07.001. View

13.

Liu F, Xia Y, Parker A, Verma I . IKK biology. Immunol Rev. 2012; 246(1):239-53. PMC: 3311052. DOI: 10.1111/j.1600-065X.2012.01107.x. View

14.

Clark K, Peggie M, Plater L, Sorcek R, Young E, Madwed J . Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2010; 434(1):93-104. DOI: 10.1042/BJ20101701. View

15.

Hjerpe R, Thomas Y, Kurz T . NEDD8 overexpression results in neddylation of ubiquitin substrates by the ubiquitin pathway. J Mol Biol. 2012; 421(1):27-9. DOI: 10.1016/j.jmb.2012.05.013. View

16.

Lammer D, Mathias N, Laplaza J, Jiang W, Liu Y, Callis J . Modification of yeast Cdc53p by the ubiquitin-related protein rub1p affects function of the SCFCdc4 complex. Genes Dev. 1998; 12(7):914-26. PMC: 316682. DOI: 10.1101/gad.12.7.914. View

17.

Senftleben U, Cao Y, Xiao G, Greten F, Krahn G, Bonizzi G . Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science. 2001; 293(5534):1495-9. DOI: 10.1126/science.1062677. View

18.

Lin L, DeMartino G, Greene W . Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell. 1998; 92(6):819-28. DOI: 10.1016/s0092-8674(00)81409-9. View

19.

Ordureau A, Enesa K, Nanda S, Le Francois B, Peggie M, Prescott A . DEAF1 is a Pellino1-interacting protein required for interferon production by Sendai virus and double-stranded RNA. J Biol Chem. 2013; 288(34):24569-80. PMC: 3750155. DOI: 10.1074/jbc.M113.479550. View

20.

Shembade N, Parvatiyar K, Harhaj N, Harhaj E . The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J. 2009; 28(5):513-22. PMC: 2657574. DOI: 10.1038/emboj.2008.285. View