Reactome | AUF1 (hnRNP D0) binds and destabilizes mRNA

AUF1 (hnRNP D0) binds and destabilizes mRNA

Stable Identifier

R-HSA-450408

Type

Pathway

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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AUF1 (hnRNP D0) binds and destabilizes mRNA

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AUF1 (hnRNP D0) dimers bind U-rich regions of AU-rich elements (AREs) in the 3' untranslated regions of mRNAs. The binding causes AUF1 dimers to assemble into higher order tetrameric complexes. Diphosphorylated AUF1 bound to RNA recruits additional proteins, including eIF4G, polyA-binding protein, Hsp, Hsc70, Hsp27, NSEP-1, NSAP-1, and IMP-2 which target the mRNA and AUF1 for degradation. Unphosphorylated AUF1 is thought to be less able to recruit additional proteins. AUF1 also interacts directly or indirectly with HuR and the RNA-induced silencing complex (RISC).
AUF1 complexed with RNA and other proteins is ubiquitinated and targeted for destruction by the proteasome while the bound mRNA is degraded. Inhibition of ubiquitin addition to AUF1 blocks mRNA degradation. The mechanism by which ubiquitin-dependent proteolysis is coupled to mRNA degradation is unknown.
At least 4 isoforms of AUF1 exist: p45 (45 kDa) contains all exons, p42 lacks exon 2, p40 lacks exon 7, and p37 lacks exons 2 and 7. The presence of exon 7 in p42 and p45 seems to block ubiquitination while the absence of exon 7 (p37 and p40) targets AUF1 for ubiquitination and destabilizes bound RNAs. Lack of exon 2 (p37 and p42) is associated with higher affinity for RNA and 14-3-3sigma (SFN).
AUF1 binds and destabilizes mRNAs encoding Interleukin-1 beta (IL1B), Tumor Necrosis Factor alpha (TNFA), Cyclin-dependent kinase inhibitor 1 (CDNK1A, p21), Cyclin-D1 (CCND1), Granulocyte-macrophage colony stimulating factor (GM-CSF, CSF2), inducible Nitric oxide synthase (iNOS, NOS2), Proto-oncogene cFos (FOS), Myc proto-oncogene (MYC), Apoptosis regulator Bcl-2 (BCL2).

Literature References

PubMed ID	Title	Journal	Year
16391004	AU-rich elements and associated factors: are there unifying principles? Barreau, C, Paillard, L, Osborne, HB	Nucleic Acids Res	2005
12704645	Post-transcriptional regulation of gene expression by degradation of messenger RNAs Ceriani, MC, Bevilacqua, A, Capaccioli, S, Nicolin, A	J Cell Physiol	2003
10205060	Control of mRNA decay by heat shock-ubiquitin-proteasome pathway Brewer, G, Schneider, RJ, Laroia, G, Cuesta, R	Science	1999
12440953	AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors Kruys, V, Zhang, T, Huez, G, Gueydan, C	Biochem Soc Trans	2002
12819195	Regulation of A + U-rich element-directed mRNA turnover involving reversible phosphorylation of AUF1 Brewer, G, Wilson, GM, Huynh, Y, Sun, Y, Lu, J, Sutphen, K	J Biol Chem	2003
18573886	Chaperone Hsp27, a novel subunit of AUF1 protein complexes, functions in AU-rich element-mediated mRNA decay Brewer, G, Sinsimer, KS, Krause, CD, Rivera, YM, Turrin, DK, Scrudato, S, Gupta, S, Wierzbowski, AV, Lu, J, Maher, LR, Knapinska, AM, Pestka, S, De La Cruz, MP, Gratacos, FM	Mol Cell Biol	2008