Nuclear Import Receptors and HnRNPK Mediates Nuclear Import and Stress Granule Localization of SIRLOIN

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2021 Oct 24

PMID 34689235

Citations 2

Authors

Jialin Yao

Yingfeng Tu

Congcong Shen

Qiao Zhou

Hengyi Xiao

Da Jia

Qingxiang Sun

Affiliations

Soon will be listed here.

Abstract

The majority of lncRNAs and a small fraction of mRNAs localize in the cell nucleus to exert their functions. A SIRLOIN RNA motif was previously reported to drive its nuclear localization by the RNA-binding protein hnRNPK. However, the underlying mechanism remains unclear. Here, we report crystal structures of hnRNPK in complex with SIRLOIN, and with the nuclear import receptor (NIR) Impα1, respectively. The protein hnRNPK bound to SIRLOIN with multiple weak interactions, and interacted Impα1 using an independent high-affinity site. Forming a complex with hnRNPK and Impα1 was essential for the nuclear import and stress granule localization of SIRLOIN in semi-permeabilized cells. Nuclear import of SIRLOIN enhanced with increasing NIR concentrations, but its stress granule localization peaked at a low NIR concentration. Collectively, we propose a mechanism of SIRLOIN localization, in which NIRs functioned as drivers/regulators, and hnRNPK as an adaptor.

Citing Articles

Structural Characteristics and Properties of the RNA-Binding Protein hnRNPK at Multiple Physical States.

Le Q, Lewis A, Dix-Matthews A, Ringler P, Duff A, Whitten A Int J Mol Sci. 2025; 26(3).

PMID: 39941124 PMC: 11818384. DOI: 10.3390/ijms26031356.

Nucleic acid-binding KH domain proteins influence a spectrum of biological pathways including as part of membrane-localized complexes.

Hasan M, Jeannine Brady L J Struct Biol X. 2024; 10:100106.

PMID: 39040530 PMC: 11261784. DOI: 10.1016/j.yjsbx.2024.100106.

Biophysical characterisation of human LincRNA-p21 sense and antisense Alu inverted repeats.

DSouza M, Mrozowich T, Badmalia M, Geeraert M, Frederickson A, Henrickson A Nucleic Acids Res. 2022; 50(10):5881-5898.

PMID: 35639511 PMC: 9177966. DOI: 10.1093/nar/gkac414.

References

Flynn R, Chang H . Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 2014; 14(6):752-61. PMC: 4120821. DOI: 10.1016/j.stem.2014.05.014. View

Statello L, Guo C, Chen L, Huarte M . Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2020; 22(2):96-118. PMC: 7754182. DOI: 10.1038/s41580-020-00315-9. View

Chen L . Linking Long Noncoding RNA Localization and Function. Trends Biochem Sci. 2016; 41(9):761-772. DOI: 10.1016/j.tibs.2016.07.003. View

Batista P, Chang H . Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013; 152(6):1298-307. PMC: 3651923. DOI: 10.1016/j.cell.2013.02.012. View

Butti Z, Patten S . RNA Dysregulation in Amyotrophic Lateral Sclerosis. Front Genet. 2019; 9:712. PMC: 6349704. DOI: 10.3389/fgene.2018.00712. View

Lubelsky Y, Ulitsky I . Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells. Nature. 2018; 555(7694):107-111. PMC: 6047738. DOI: 10.1038/nature25757. View

Wang Z, Qiu H, He J, Liu L, Xue W, Fox A . The emerging roles of hnRNPK. J Cell Physiol. 2019; 235(3):1995-2008. DOI: 10.1002/jcp.29186. View

Xu Y, Wu W, Han Q, Wang Y, Li C, Zhang P . Post-translational modification control of RNA-binding protein hnRNPK function. Open Biol. 2019; 9(3):180239. PMC: 6451366. DOI: 10.1098/rsob.180239. View

Hutchins E, Belrose J, Szaro B . A novel role for the nuclear localization signal in regulating hnRNP K protein stability in vivo. Biochem Biophys Res Commun. 2016; 478(2):772-6. DOI: 10.1016/j.bbrc.2016.08.023. View

10.

Lange A, Mills R, Lange C, Stewart M, Devine S, Corbett A . Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2006; 282(8):5101-5. PMC: 4502416. DOI: 10.1074/jbc.R600026200. View

11.

Youn J, Dyakov B, Zhang J, Knight J, Vernon R, Forman-Kay J . Properties of Stress Granule and P-Body Proteomes. Mol Cell. 2019; 76(2):286-294. DOI: 10.1016/j.molcel.2019.09.014. View

12.

Chang W, Tarn W . A role for transportin in deposition of TTP to cytoplasmic RNA granules and mRNA decay. Nucleic Acids Res. 2009; 37(19):6600-12. PMC: 2770677. DOI: 10.1093/nar/gkp717. View

13.

Moujalled D, James J, Yang S, Zhang K, Duncan C, Moujalled D . Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. Hum Mol Genet. 2014; 24(6):1655-69. DOI: 10.1093/hmg/ddu578. View

14.

Khong A, Matheny T, Jain S, Mitchell S, Wheeler J, Parker R . The Stress Granule Transcriptome Reveals Principles of mRNA Accumulation in Stress Granules. Mol Cell. 2017; 68(4):808-820.e5. PMC: 5728175. DOI: 10.1016/j.molcel.2017.10.015. View

15.

Zhang K, Daigle J, Cunningham K, Coyne A, Ruan K, Grima J . Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018; 173(4):958-971.e17. PMC: 6083872. DOI: 10.1016/j.cell.2018.03.025. View

16.

Yoga Y, Traore D, Sidiqi M, Szeto C, Pendini N, Barker A . Contribution of the first K-homology domain of poly(C)-binding protein 1 to its affinity and specificity for C-rich oligonucleotides. Nucleic Acids Res. 2012; 40(11):5101-14. PMC: 3367169. DOI: 10.1093/nar/gks058. View

17.

Martin E, Holehouse A, Peran I, Farag M, Incicco J, Bremer A . Valence and patterning of aromatic residues determine the phase behavior of prion-like domains. Science. 2020; 367(6478):694-699. PMC: 7297187. DOI: 10.1126/science.aaw8653. View

18.

Gao Y, Pei G, Li D, Li R, Shao Y, Zhang Q . Multivalent mA motifs promote phase separation of YTHDF proteins. Cell Res. 2019; 29(9):767-769. PMC: 6796879. DOI: 10.1038/s41422-019-0210-3. View

19.

Backe P, Messias A, Ravelli R, Sattler M, Cusack S . X-ray crystallographic and NMR studies of the third KH domain of hnRNP K in complex with single-stranded nucleic acids. Structure. 2005; 13(7):1055-67. DOI: 10.1016/j.str.2005.04.008. View

20.

Braddock D, Baber J, Levens D, Clore G . Molecular basis of sequence-specific single-stranded DNA recognition by KH domains: solution structure of a complex between hnRNP K KH3 and single-stranded DNA. EMBO J. 2002; 21(13):3476-85. PMC: 126100. DOI: 10.1093/emboj/cdf352. View