Staufen-mediated mRNA decay

Staufen-mediated mRNA decay (SMD) is a metabolic pathway that leads to degradation of specific mRNA transcripts mediated by Staufen protein. According to bioinformatic predictations, more than 1,000 mRNA transcripts could potentially be target by SMD.[1] SMD occurs when SMD factors (like UPF1 and UPF2) bind to staufen in stem-loop elements of the 3'UTR.[2]

Staufen-mediated mRNA decay [3]

SMD factors like UPF1 and UPF2 factors cleave the mRNAs bound to Staufen.[4][5][6][7][8]

Discovery

Staufen was previously known to interact and transport mRNA into the cytoplasm in Drosophila melanogaster.[9] This protein was also known to activate gene expression in Oskar gene once it is localized in Drosophila posterior pole.[10] Staufen null mutants in Drosophila malanogaster are alive, but their embryos failed to develop living flies, therefore, the name comes after Staufen dynasty where all male offsprings died before reproducing. [2]

However, the excact mechanisms used by Staufen to affect gene expression were unknown. Finally in 2005, Staufen-mediated mRNA decay was identified when a protein known to be involved in a similar metabolism (non-sense mediated mRNA decay) was bound to Staufen. [11]

Mechanism

SMD occurs when staufen protein binds to an mRNA and recruits SMD factors (UPF1, UPF2) that degrade the RNA molecule bound to Staufen. SMD may involve gene expression in more than 1000 mRNA transcripts. SMD is reported to be a stepwise process: 1) two Staufen protein particles bind target mRNA by their double-stranded RNA binding domain (dsRBD) 3 and 4, 2) the two Staufen particles dimerizes by establishing non-covalent interactions between their Staufen-swapping motif (SSM) and dsRBD5 located in their C' termini, 3) this dimerized staufen complex is recognized by SMD factors (i.e. UPF1, UPF2). It was reported that, upon SSM deletion, staufen particles bind to target mRNA but fail to dimerize and form a non-dimerized staufen complex. This complex inhibits SMD.[3]

References

  1. ↑ Lucas, Bronwyn A.; Lavi, Eitan; Shiue, Lily; Cho, Hana; Katzman, Sol; Miyoshi, Keita; Siomi, Mikiko C.; Carmel, Liran; Ares, Manuel; Maquat, Lynne E. (2018-01-30). "Evidence for convergent evolution of SINE-directed Staufen-mediated mRNA decay". Proceedings of the National Academy of Sciences. 115 (5): 968–973. doi:10.1073/pnas.1715531115. PMC 5798355. PMID 29339519.
  2. 1 2 Park, Eonyoung; Maquat, Lynne E. (2013). "Staufen-mediated mRNA decay". Wires RNA. 4 (4): 423–435. doi:10.1002/wrna.1168. PMC 3711692. PMID 23681777.
  3. 1 2 Tripepi, Andrea; Shakoor, Huma; Zlobina, Maria; Klumpler, Tomáš; Kubíčková, Monika; Houser, Josef; Klapetek, Petr; Lukavsky, Peter Josef (2026). "Staufen-swapping motif is crucial for Staufen dimerization, structure, and Staufen-mediated mRNA decay". Protein Science. 35 (7) e70669. doi:10.1002/pro.70669. ISSN 1469-896X. PMC 13270411. PMID 42300088.
  4. ↑ Gleghorn, Michael L.; Gong, Chenguang; Kielkopf, Clara L.; Maquat, Lynne E. (April 2013). "Staufen1 dimerizes through a conserved motif and a degenerate dsRNA-binding domain to promote mRNA decay". Nature Structural & Molecular Biology. 20 (4): 515–524. doi:10.1038/nsmb.2528. ISSN 1545-9985. PMC 4096160. PMID 23524536.
  5. ↑ Park, Eonyoung; Gleghorn, Michael L.; Maquat, Lynne E. (2013-01-08). "Staufen2 functions in Staufen1-mediated mRNA decay by binding to itself and its paralog and promoting UPF1 helicase but not ATPase activity". Proceedings of the National Academy of Sciences. 110 (2): 405–412. doi:10.1073/pnas.1213508110. ISSN 0027-8424. PMC 3545820. PMID 23263869.
  6. ↑ Park, Eonyoung; Maquat, Lynne E. (2013). "Staufen-mediated mRNA decay". WIREs RNA. 4 (4): 423–435. doi:10.1002/wrna.1168. ISSN 1757-7012. PMC 3711692. PMID 23681777.
  7. ↑ Gowravaram, Manjeera; Schwarz, Juliane; Khilji, Sana K.; Urlaub, Henning; Chakrabarti, Sutapa (2019-11-07). "Insights into the assembly and architecture of a Staufen-mediated mRNA decay (SMD)-competent mRNP". Nature Communications. 10 (1): 5054. doi:10.1038/s41467-019-13080-x. ISSN 2041-1723. PMC 6838198. PMID 31699982.
  8. ↑ Kim, Yoon Ki; Furic, Luc; DesGroseillers, Luc; Maquat, Lynne E. (January 2005). "Mammalian Staufen1 Recruits Upf1 to Specific mRNA 3′UTRs so as to Elicit mRNA Decay". Cell. 120 (2): 195–208. doi:10.1016/j.cell.2004.11.050. ISSN 0092-8674. PMID 15680326.
  9. ↑ Marión, Rosa María; Fortes, Puri; Beloso, Ana; Dotti, Carlos; Ortín, Juan (1999). "A Human Sequence Homologue of Staufen is an RNA-Binding Protein That is Associated with Polysomes and Localizes to the Rough Endoplasmic Reticulum". Molecular and Cellular Biology. 19 (3): 2212–2219. doi:10.1128/MCB.19.3.2212. PMC 84014. PMID 10022908.
  10. ↑ Ephrussi, Anne; Dickinson, Laura K.; Lehmann, Ruth (1991). "Oskar organizes the germ plasm and directs localization of the posterior determinant nanos". Cell. 66 (1): 37–50. doi:10.1016/0092-8674(91)90137-n. PMID 2070417.
  11. ↑ Kim, Yoon Ki; Furic, Luc; Desgroseillers, Luc; Maquat, Lynne E. (2005). "Mammalian Staufen1 Recruits Upf1 to Specific mRNA 3′UTRs so as to Elicit mRNA Decay". Cell. 120 (2): 195–208. doi:10.1016/j.cell.2004.11.050. PMID 15680326.
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