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Karyopherin-mediated nucleocytoplasmic transport

Abstract

Efficient and regulated nucleocytoplasmic trafficking of macromolecules to the correct subcellular compartment is critical for proper functions of the eukaryotic cell. The majority of the macromolecular traffic across the nuclear pores is mediated by the Karyopherin-β (or Kap) family of nuclear transport receptors. Work over more than two decades has shed considerable light on how the different Kap family members bring their respective cargoes into the nucleus or the cytoplasm in efficient and highly regulated manners. In this Review, we overview the main features and established functions of Kap family members, describe how Kaps recognize their cargoes and discuss the different ways in which these Kap–cargo interactions can be regulated, highlighting new findings and open questions. We also describe current knowledge of the import and export of the components of three large gene expression machines — the core replisome, RNA polymerase II and the ribosome — pointing out the questions that persist about how such large macromolecular complexes are trafficked to serve their function in a designated subcellular location.

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Fig. 1: Kap-mediated nucleocytoplasmic transport and principles of Kap–cargo interactions and RAN–GTP-dependent loading/unloading.
Fig. 2: Comparison of unliganded, cargo-bound and RAN-bound importins.
Fig. 3: Comparison of unliganded, cargo-bound and RAN-bound exportins and biportins.
Fig. 4: Regulation of Kap–cargo interactions.
Fig. 5: Nuclear trafficking of three different gene expression machineries.

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Acknowledgements

This work was funded by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Awards R01GM069909 and R35GM144137 (Y.M.C.), the Welch Foundation Grant I-1532 (Y.M.C.), Cancer Prevention Research Institute of Texas (CPRIT) Grant RP180410 (Y.M.C.), support from the Alfred and Mabel Gilman Chair in Molecular Pharmacology, Eugene McDermott Scholar in Biomedical Research (Y.M.C.), the Gilman Special Opportunities Award (H.Y.J.F.) and NIGMS Molecular Biophysics Training Program T32GM131963 (C.E.W.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Ho Yee Joyce Fung or Yuh Min Chook.

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Y.M.C. is a consultant for Faze Medicines. The remaining authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks Anita Corbett, Roderick Lim and Michael Rout for their contribution to the peer review of this work.

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Related links

cNLS Mapper: http://nls-mapper.iab.keio.ac.jp

INSP: http://www.csbio.sjtu.edu.cn/bioinf/INSP/

LocNES: http://prodata.swmed.edu/LocNES/LocNES.php

NESmapper: https://sourceforge.net/projects/nesmapper/

NetNES: https://services.healthtech.dtu.dk/service.php?NetNES-1.1

NLStradamus: http://www.moseslab.csb.utoronto.ca/NLStradamus/

NoLogo: https://github.com/mppl1/NoLogo

NucPred: https://nucpred.bioinfo.se/nucpred/

NucImport: http://bioinf.scmb.uq.edu.au:8080/NucImport/

PSORT: https://www.genscript.com/psort.htmlPSORT II: https://psort.hgc.jp/form2.html

PredictNLS: https://rostlab.org/owiki/index.php/PredictNLS

SeqNLS: http://mleg.cse.sc.edu/seqNLS/

Wregex: http://ehubio.ehu.eus/wregex/home.xhtml

Supplementary information

Glossary

Nanobodies

Small, single-domain antibodies derived from camelids (camels, alpacas and llamas) that lack light chains.

HEAT repeats

Structural motifs composed of two antiparallel α-helices that are usually connected by a loop. HEAT repeats occur in tandem to form solenoid or superhelical structures.

Intrinsically disordered regions

(IDRs). Protein regions that do not have persistent tertiary structures.

Armadillo (ARM) repeat domain

A protein domain typically 40 residues long that shares homology with repeating units in the ARM protein family. It contains two or three helices per repeat, which stack into a solenoid arrangement.

Amyotrophic lateral sclerosis

A fatal neurodegenerative disease, with progressive loss of motor neuron control that leads to paralysis. Amyotrophic lateral sclerosis onset and progression may be a consequence of protein misfolding/aggregation.

Exon junction complex

A multiprotein complex that binds to the junction between exons in nuclear precursor mRNAs and remains bound during their export to the cytoplasm.

MH2 domain

A protein domain found in the carboxy-terminal portion of SMAD proteins. It comprises a β-sandwich fold with a three-helix bundle on one end and a loop–helix region on the other.

SH3-like domain

A small globular domain that binds poly-proline motifs, comprising five or six β-strands tightly packed into antiparallel β-sheets.

OB domain

A small globular domain composed of two three-stranded antiparallel β-strands packed into a flattened β-barrel.

Machine learning

A branch of artificial intelligence that automates iterative analytical model building based solely on training data, with minimal human intervention.

m3G cap

A 2,2,7-trimethylated guanosine cap structure of uridylate-rich small nuclear RNAs (U small nuclear RNAs), which are the RNA components of spliceosomal ribonucleoproteins (small nuclear RNP).

Multisystem proteinopathy

A group of inherited disorders that cause neurodegeneration, myopathy and bone disease, and can manifest as amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, Paget’s disease of bone or their combination.

P-body

A type of cytoplasmic granule containing mRNAs and proteins that is involved in RNA metabolism with liquid droplet properties.

MEX67-MTR2

A heterodimeric mRNA export receptor that also functions in ribosomal export and is conserved in eukaryotes.

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Wing, C.E., Fung, H.Y.J. & Chook, Y.M. Karyopherin-mediated nucleocytoplasmic transport. Nat Rev Mol Cell Biol 23, 307–328 (2022). https://doi.org/10.1038/s41580-021-00446-7

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