ELAV-like protein 1 orHuR (human antigen R) is aprotein that in humans is encoded by theELAVL1gene.[5][6]
The protein encoded by this gene is a member of the ELAVL protein family. This encoded protein contains 3 RNA-binding domains and binds cis-actingAU-rich elements in3' untranslated regions. One of its best-known functions is to stabilizemRNAs in order to regulate gene expression.[7] Variouspost-translational modifications of HuR influence itssubcellular localization and stability of binding to mRNAs.[8]
Of the RNA-binding ELAV/Hu family of proteins in mammals, HuR is the onlyubiquitously expressed one, whereas the other three are primarily found in neuronal tissue.[9] Having a well-conserved primary structure to its family members, HuR has two adjacent RNA recognition motifs (RRMs) proximal to theN-terminus, followed by a flexible hinge region next to a final RRM at theC-terminus.[5] The RRM domains of HuR each contain two alpha helices with several antiparallel beta sheets in theirsecondary structure, a 20 amino-acid long N-terminus before RRM1 and RRM2, and a 12 amino acid linker connecting them.[10][11] The hinge region connecting RRM1,2 to RRM3 is 60 amino acids long.[11]
The RRM1 domain appears to be the principal RNA-binding portion with RRM2 contributing some more contacts.[11] According to crystal structure studies, RRM1,2 domains correspond to a "moderately specific" predictedconsensus sequence.[12][13] Additionally, RRM3 contributes todimerization andoligomerization of HuR, supporting binding to AU-rich elements of RNA by the other domains, but RRM3 itself has moderate binding strength to RNA.[12] RRM3 has been shown to bind to longpoly-A tails and AU-rich RNAs.[14]
This RNA-binding protein has been found to be involved in a number of valuable cellular processes in mammals, including embryonic development, stress responses, and the immune system.[15] Post-translational modifications of HuR, includingphosphorylation,NEDDylation,methylation, andubiquitination each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter theaffinity of HuR to RNA.[8] As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript.[16]
Phosphorylation of HuR can occur bycyclin-dependent kinases (cdks), impacting its localization within the cell in a cell cycle-dependent fashion.[17] Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR duringgenotoxic stress, promoting dissociation of HuR from its target mRNA transcript.[18]
Additionally, the ubiquitination of HuR by anE3 ligase in many cases results inproteasomal degradation. For instance, the esophageal tumor suppressor ECRG2, ubiquitinates HuR during DNA damage, promoting its degradation.[19] However, in other cases, ubiquitination promotes dissociation of HuR from its transcript, such as ubiquitination of certainlysine residues of the RRM3 domain leading to detachment from the mRNA transcript ofP21 and other tumor suppressors.[20]
Moreover, as is frequent in other mammalian proteins, HuR is methylated at arginine residues.[21] For instance, protein argininemethyltransferase enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such asSIRT1 inHeLa cells.[22]
HuR has been shown to inhibit biogenesis ofmiR-7.[23][24] Small molecules have been shown to target HuR/RNA interactions with a functional outcome on the downstream targets.[25][26]
Although HuR has a vital role intranscriptosomal regulation, there is an apparent up-regulation of HuR in several types of cancer that correlates with a malignant or metastatic status that has increased the relevance of HuR as a potential therapeutic target for a number of cancer studies. The abundance of HuR suggests a tumorigenic promotion ofangiogenesis, cellular proliferation, and anti-apoptotic properties in cancer cells, purportedly due to the impact of mRNA stabilization and its ubiquitous presence in human tissue.[27]
^abDoller A, Pfeilschifter J, Eberhardt W (December 2008). "Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR".Cellular Signalling.20 (12):2165–2173.doi:10.1016/j.cellsig.2008.05.007.PMID18585896.
^Cléry A, Blatter M, Allain FH (June 2008). "RNA recognition motifs: boring? Not quite".Current Opinion in Structural Biology.18 (3):290–298.doi:10.1016/j.sbi.2008.04.002.PMID18515081.
^abcWang H, Zeng F, Liu Q, Liu H, Liu Z, Niu L, et al. (March 2013). "The structure of the ARE-binding domains of Hu antigen R (HuR) undergoes conformational changes during RNA binding".Acta Crystallographica. Section D, Biological Crystallography.69 (Pt 3):373–380.doi:10.1107/S0907444912047828.PMID23519412.
^Wang X, Tanaka Hall TM (February 2001). "Structural basis for recognition of AU-rich element RNA by the HuD protein".Nature Structural Biology.8 (2):141–145.doi:10.1038/84131.PMID11175903.
^Lucchesi C, Sheikh MS, Huang Y (May 2016). "Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2".Oncogene.35 (20):2565–2573.doi:10.1038/onc.2015.339.PMID26434587.
^Lebedeva S, Jens M, Theil K, Schwanhäusser B, Selbach M, Landthaler M, et al. (August 2011). "Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR".Molecular Cell.43 (3):340–352.doi:10.1016/j.molcel.2011.06.008.PMID21723171.
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