Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity

Overview

Journal Front Physiol

Date 2020 Nov 16

PMID 33192571

Citations 11

Authors

Donald W Lawrence

Paul A Willard

Allyson M Cochran

Emily C Matchett

Jacki Kornbluth

Affiliations

Soon will be listed here.

Abstract

Natural Killer Lytic-Associated Molecule (NKLAM), also designated RNF19B, is a unique member of a small family of E3 ubiquitin ligases. This 14-member group of ligases has a characteristic cysteine-rich RING-IBR-RING (RBR) domain that mediates the ubiquitination of multiple substrates. The consequence of substrate ubiquitination varies, depending on the type of ubiquitin linkages formed. The most widely studied effect of ubiquitination of proteins is proteasome-mediated substrate degradation; however, ubiquitination can also alter protein localization and function. Since its discovery in 1999, much has been deciphered about the role of NKLAM in innate immune responses. We have discerned that NKLAM has an integral function in both natural killer (NK) cells and macrophages and . NKLAM expression is required for each of these cell types to mediate maximal killing activity and cytokine production. However, much remains to be determined. In this review, we summarize what has been learned about NKLAM expression, structure and function, and discuss new directions for investigation. We hope that this will stimulate interest in further exploration of NKLAM.

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References

Malhotra D, Darvishi K, Lohra M, Kumar H, Grover C, Sood S . Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Eur J Hum Genet. 2006; 14(4):438-42. DOI: 10.1038/sj.ejhg.5201563. View

Wu C, Li J, Li L, Sun J, Fabbri M, Wayne A . Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. J Extracell Vesicles. 2019; 8(1):1588538. PMC: 6419691. DOI: 10.1080/20013078.2019.1588538. View

Herb M, Gluschko A, Schramm M . LC3-associated phagocytosis - The highway to hell for phagocytosed microbes. Semin Cell Dev Biol. 2019; 101:68-76. DOI: 10.1016/j.semcdb.2019.04.016. View

Sarraf S, Raman M, Guarani-Pereira V, Sowa M, Huttlin E, Gygi S . Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013; 496(7445):372-6. PMC: 3641819. DOI: 10.1038/nature12043. View

Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R . The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell. 2005; 123(3):409-21. DOI: 10.1016/j.cell.2005.08.016. View

Smit J, Sixma T . RBR E3-ligases at work. EMBO Rep. 2014; 15(2):142-54. PMC: 3989860. DOI: 10.1002/embr.201338166. View

Yao F, Zhou Z, Kim J, Hang Q, Xiao Z, Ton B . SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nat Commun. 2018; 9(1):2269. PMC: 5995870. DOI: 10.1038/s41467-018-04620-y. View

Ewens A, Mihich E, Ehrke M . Distant metastasis from subcutaneously grown E0771 medullary breast adenocarcinoma. Anticancer Res. 2005; 25(6B):3905-15. View

Dyson H . Making Sense of Intrinsically Disordered Proteins. Biophys J. 2016; 110(5):1013-6. PMC: 4788759. DOI: 10.1016/j.bpj.2016.01.030. View

10.

Gullickson G, Ambrose E, Hoover R, Kornbluth J . Uridine Cytidine Kinase Like-1 Enhances Tumor Cell Proliferation and Mediates Protection from Natural Killer-Mediated Killing. Int J Immunol Immunother. 2020; 3(1). PMC: 7032549. DOI: 10.23937/2378-3672/1410018. View

11.

Lawrence D, Shornick L, Kornbluth J . Mice deficient in NKLAM have attenuated inflammatory cytokine production in a Sendai virus pneumonia model. PLoS One. 2019; 14(9):e0222802. PMC: 6754162. DOI: 10.1371/journal.pone.0222802. View

12.

Cheng W, Tao H, Hu E, Liu S, Cai H, Tao X . Both genes and lncRNAs can be used as biomarkers of prostate cancer by using high throughput sequencing data. Eur Rev Med Pharmacol Sci. 2014; 18(22):3504-10. View

13.

Huntelmann B, Staab J, Herrmann-Lingen C, Meyer T . A conserved motif in the linker domain of STAT1 transcription factor is required for both recognition and release from high-affinity DNA-binding sites. PLoS One. 2014; 9(5):e97633. PMC: 4029728. DOI: 10.1371/journal.pone.0097633. View

14.

Portis T, Anderson J, Esposito A, Kornbluth J . Gene structure of human and mouse NKLAM, a gene associated with cellular cytotoxicity. Immunogenetics. 2000; 51(7):546-55. DOI: 10.1007/s002510000182. View

15.

Luo L, Zhu D, Huang R, Xiong L, Mehjabin R, He L . Molecular cloning and preliminary functional analysis of six RING-between-ring (RBR) genes in grass carp (Ctenopharyngodon idellus). Fish Shellfish Immunol. 2019; 87:62-72. DOI: 10.1016/j.fsi.2018.12.078. View

16.

Manzanillo P, Ayres J, Watson R, Collins A, Souza G, Rae C . The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature. 2013; 501(7468):512-6. PMC: 3886920. DOI: 10.1038/nature12566. View

17.

Lawrence D, Kornbluth J . E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity. Cell Signal. 2016; 28(12):1833-1841. PMC: 5206800. DOI: 10.1016/j.cellsig.2016.08.014. View

18.

Diefenbach A, Jensen E, Jamieson A, Raulet D . Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001; 413(6852):165-71. PMC: 3900321. DOI: 10.1038/35093109. View

19.

Kaneko M, Iwase I, Yamasaki Y, Takai T, Wu Y, Kanemoto S . Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation. Sci Rep. 2016; 6:30955. PMC: 4971459. DOI: 10.1038/srep30955. View

20.

Metzger M, Pruneda J, Klevit R, Weissman A . RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2013; 1843(1):47-60. PMC: 4109693. DOI: 10.1016/j.bbamcr.2013.05.026. View