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Nascent Chain-Mediated Localization of mRNA on the Endoplasmic Reticulum as an Important Step of Unfolded Protein Response

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Regulatory Nascent Polypeptides

Abstract

A system for homeostatic control of proteome, namely proteostasis, in a cell is conserved through a wide range of living organisms. The system is composed of a sensor for misfolded proteins that arise from perturbed proteostasis and signaling machinery that induces the expression of genes for molecular chaperones and proteolytic factors to counterbalance the proteostasis perturbation. In eukaryotes, distinct cellular response mechanisms have been elaborated for perturbed proteostasis within each organelle. In these cases, a sensor molecule recognizes misfolded proteins in the organelle and somehow transmits the signal to the nucleus across the organelle membrane. In the case of the endoplasmic reticulum (ER), proteostatic perturbation is sensed by an ER-resident transmembrane endoribonuclease inositol requiring 1 (IRE1) that catalyzes unconventional splicing of a precursor mRNA on the ER membrane. The resulting spliced form of the mRNA encodes a transcription factor that enters the nucleus and evokes a cellular response to counterbalance the perturbed proteostasis by activating transcription of target genes. In this chapter, we discuss the recently characterized mechanism, in which a nascent polypeptide encoded by the splicing-substrate mRNA directs localization of its own mRNA onto the ER membrane as an essential step for the efficient unconventional splicing of the substrate mRNA upon ER stresses. In particular, we focus on the mechanism that targets the unspliced precursor form of X-box binding protein 1 (XBP1u) mRNA to the ER membrane in metazoan cells. Importantly, translational pausing plays pivotal roles that ensure the nascent chain-mediated ER-targeting of XBP1u mRNA. We also discuss the prerequisites and generality of nascent chain-mediated mRNA localization in the cell.

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Abbreviations

BiP:

Immunoglobulin heavy chain binding protein

CTR:

Carboxy-terminal region

ER:

Endoplasmic reticulum

ERAD:

ER associated degradation

HSP:

Heat shock protein

HSF:

Heat shock factor

HAC1:

Homologous to ATF/CREB 1

IRE1:

Inositol requiring 1

ORF:

Open reading frame

HR2:

Hydrophobic region 2

R-RNC:

mRNA–ribosome–nascent chain complex

SRP:

Signal recognition particle

SR:

SRP receptor

UPR:

Unfolded protein response

UPRE:

UPR element

UTR:

Untranslated region

XBP1:

X-box binding protein 1

XBP1u:

Unspliced form of XBP1

XBP1s:

Spliced form of XBP1

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Acknowledgments

We thank Drs. Hiroshi Kadokura and Koreaki Ito for discussion and support in writing this paper. This work was supported by Grants-in-Aid for Research Activity Start-up (K.Y.), Scientific Research (B) and (S) (K.K.), and Scientific Research on Priority Areas (K.K.) of KAKENHI from The Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara, 630-0192, Japan

    Kota Yanagitani & Kenji Kohno

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  1. Kota Yanagitani
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  2. Kenji Kohno
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Correspondence to Kenji Kohno .

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Editors and Affiliations

  1. Kyoto Sangyo University, Kita-ku, Kyoto, Japan

    Koreaki Ito

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Yanagitani, K., Kohno, K. (2014). Nascent Chain-Mediated Localization of mRNA on the Endoplasmic Reticulum as an Important Step of Unfolded Protein Response. In: Ito, K. (eds) Regulatory Nascent Polypeptides. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55052-5_17

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