ELAV-like protein 1 or HuR (human antigen R) is a protein that in humans is encoded by the ELAVL1gene.[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-acting AU-rich elements in 3' untranslated regions. One of its best-known functions is to stabilize mRNAs in order to regulate gene expression.[7] Various post-translational modifications of HuR influence its subcellular localization and stability of binding to mRNAs.[8]
Structure
Of the RNA-binding ELAV/Hu family of proteins in mammals, HuR is the only ubiquitously 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 the N-terminus, followed by a flexible hinge region next to a final RRM at the C-terminus.[5] The RRM domains of HuR each contain two alpha helices with several antiparallel beta sheets in their secondary 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]
RNA Binding
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" predicted consensus sequence.[12][13] Additionally, RRM3 contributes to dimerization and oligomerization 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 long poly-A tails and AU-rich RNAs.[14]
Function
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, including phosphorylation, NEDDylation, methylation, and ubiquitination each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter the affinity of HuR to RNA.[16] As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript.[17]
Phosphorylation of HuR can occur by cyclin-dependent kinases (cdks), impacting its localization within the cell in a cell cycle-dependent fashion.[18] Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR during genotoxic stress, promoting dissociation of HuR from its target mRNA transcript.[19]
Additionally, the ubiquitination of HuR by an E3 ligase in many cases results in proteasomal degradation. For instance, the esophageal tumor suppressor ECRG2, ubiquitinates HuR during DNA damage, promoting its degradation.[20] However, in other cases, ubiquitination promotes dissociation of HuR from its transcript, such as ubiquitination of certain lysine residues of the RRM3 domain leading to detachment from the mRNA transcript of P21 and other tumor suppressors.[21]
Moreover, as is frequent in other mammalian proteins, HuR is methylated at arginine residues.[22] For instance, protein arginine methyltransferase enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such as SIRT1 in HeLa cells.[23]
Cancer
Although HuR has a vital role in transcriptosomal 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 of angiogenesis, cellular proliferation, and anti-apoptotic properties in cancer cells, purportedly due to the impact of mRNA stabilization and its ubiquitous presence in human tissue.[24]
^Doller 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.
^Doller 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.
^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.
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