Factors influencing the nuclear targeting ability of nuclear localization signals

Sun, Yanping; Xian, Lei; Xing, Haonan; Yu, Jie-Ping; Yang, Zhen; Yang, Tianzhi; Yang, Li; Ding, Pingtian

doi:10.1080/1061186x.2016.1184273

Cited by 34 publications

(27 citation statements)

References 87 publications

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“…NLSs are short amino acid sequences and can be divided into two categories: classical and non‐classical sequences. Classical NLSs consist of a cluster of basic amino acids or two basic residues separated by 10–12 neutral residues; and non‐classical NLSs lack the basic amino acid segment (Sun et al, 2016). In the NLS‐mediated nuclear transport, the NLS peptide first binds to the armadillo domain of the adaptor protein importin α and then dimerizes with the importin β to form a nuclear pore–targeting complex.…”

Section: The Structural Basis Of Cell Nuclear Transport Processmentioning

confidence: 99%

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

Zou

Feng

et al. 2020

Cell Biology International

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Nuclear‐cytoplasmic transport is necessary for the biological function of nuclear proteins. The mechanism underlying this process is very complex and has been a subject of intense research. Yes‐associated protein (YAP), a Hippo signaling pathway effector, localizes to both the cytoplasm and the nucleus and can influence cell proliferation, stem cell status, and tissue homeostasis. Recent studies have focused on the significance of YAP distribution between the nucleus and the cytoplasm in disease, but it remains unclear how this dynamic process is regulated. In this review, we discuss YAP nuclear‐cytoplasmic transport under different physiological and pathological conditions in terms of mechanical signaling, protein modification, and metabolism. Understanding the mechanisms underlying nuclear‐cytoplasmic YAP transport mechanism under different physiological and pathological conditions may help identify important targets for disease treatment.

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Section: The Structural Basis Of Cell Nuclear Transport Processmentioning

confidence: 99%

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

Zou

Feng

et al. 2020

Cell Biology International

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“…Although the term 'nuclear transport' can have different meanings between scientists studying basic mechanisms and those interested in therapy, the development of SV40 NLS-modified agents is an area of research that is actively investigated (49)(50)(51)(52)(53)(54). However, the general consensus is the mechanism for these NLS-containing drugs is dependent on the importin-α/importin-β complex to achieve nuclear localization (52)(53)(54)(55). Our results clearly indicate that the SV40 NLS as part of Accum is dependant on non-classical nuclear transport.…”

Section: Discussionmentioning

confidence: 99%

Proteomic-based evaluation of nuclear transport of NLS-tagged trastuzumab-emtansine with enhanced cytotoxic potency

Lacasse

Beaudoin

Jean³

et al. 2019

Preprint

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Nuclear transport receptors (NTRs) are the only proteins able to transport large molecular weight payloads into the nucleus. A dominant area of molecular therapeutic research is the extension of the use of NTRs to target the nucleus for the development of pharmaceuticals or as tools for investigating fundamental biological questions. Although several examples of synthesized peptides harbouring nuclear localization signal (NLS) sequences conjugated to various payloads exist in the literature, the assumption has been that transport occurs by classical nuclear localization via the NTRs importin-α and importin-β. This assumption is relevant to nuclear-targeted therapeutics that aim for full potential clinical impact. In addition, fundamental research can benefit from unbiased approaches to investigate the role of NTRs. Herein, we report the construction of a novel NLS-modified agent composed of trastuzumab-emtansine (T-DM1) coupled to cell accumulator (Accum), a technology that enables monoclonal antibodies to escape endosome entrapment and accumulate conjugated payloads in the nucleus without abrogating affinity or specificity to target antigens. Accum harbours a classical NLS sequence from SV-40 large T-antigen. We demonstrate that routing T-DM1 to the nucleus successfully increased cytotoxic potency in the HER2-positive cell line SKBR3. More importantly, through the development of a novel bait-prey proteomic approach, we show that the non-classical NTR importin 7 and not importin-α/importin-β was required for the cytotoxicity effect. This result was validated by siRNA knock down. Our findings also indicate that by discovering an unanticipated NTR regulator of an NLS-modified agent, this study demonstrates the utility of combining an unbiased proteomic approach to probe NTR function in mammalian cell system and, is a foresight for future NLS-based development initiatives.FRQS-funded Centre de recherche du CHUS. S.J. and J.V.L also hold faculty salary awards from FRQS. Dr. Myriam Badr for discussions about stability data. DECLARATION OF INTEREST STATEMENTNo potential conflicts of interest were disclosed Author ContributionsConception and design: V. L. prepared and characterized ADCs, designed the proteomic approach, performed all experiments, and co-wrote manuscript. S.B and S.J helped conceptualize experiments and to interpret data. J.V.L conceptualized and directed the overall approach and co-wrote the manuscript.

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“…The NLS peptides have been widely used for non‐viral gene transfer and shown potential ability to improve nuclear delivery of DNA. It means that NLS peptides may mediate the cargo's targeted regions of transcription nearby the nuclear pores . To enhance the targeting ability to endothelial cells (ECs), our groups designed a series of multifunctional peptides REDV‐G m ‐TAT‐G m ‐NLS (m = 0, 1 and 4), and our previous studies demonstrated that these multifunctional peptides could enhance the cellular uptake and nuclear localization ability …”

Section: The Remaining Percent Of the Fluorescence Intensity In Fluormentioning

confidence: 99%

Multifunctional Gene Carriers Labeled by Perylene Diimide Derivative as Fluorescent Probe for Tracking Gene Delivery

Hao

Guo

et al. 2019

Macromol. Rapid Commun.

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Multifunctional carriers with both gene transfection property and fluorescent tracking function have attracted significant attention in recent years. Herein, a kind of perylene diimide derivative (PDI‐C10C8) is conjugated onto the polyethylenimine‐g‐poly(lactide‐co‐glycolide)‐g‐polyethylenimine (PLGA‐PEI) polymer to obtain fluorescent multifunctional polymer and micelles (abbreviated as MP). Then, the REDV‐G‐TAT‐G‐NLS (TP‐G) peptide sequence is grafted onto this MP to obtain multifunctional micelles labeled by perylene diimide derivative (MP‐TP‐G). These micelles exhibit enhanced photobleaching stability compared with the reference Cy5‐labeled micelles, and the fluorescent images of cellular uptake show bright red emission without any background noise. Confocal laser scanning microscope (CLSM) experiments show that gene complexes can deliver gene into nucleus. MP‐TP‐G carriers do not enter into the cell nucleus, which proves that the nuclear localization signal sequence may not exert its nucleus accumulation ability via conjugating to the amphiphilic polymers. The high transfection efficiency and the enhanced photobleaching stability, combined with the ability to monitor the detailed process of cellular uptake and gene delivery, make these multifunctional micelles have great potential application for endothelialization of artificial blood vessels and gene delivery process study.

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Factors influencing the nuclear targeting ability of nuclear localization signals

Cited by 34 publications

References 87 publications

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

Proteomic-based evaluation of nuclear transport of NLS-tagged trastuzumab-emtansine with enhanced cytotoxic potency

Multifunctional Gene Carriers Labeled by Perylene Diimide Derivative as Fluorescent Probe for Tracking Gene Delivery

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