Dataset Information

Piggybacking on Classical Import and Other Non-Classical Mechanisms of Nuclear Import Appear Highly Prevalent within the Human Proteome.

ABSTRACT: One of the most conserved cellular pathways among eukaryotes is the extensively studied classical protein nuclear import pathway mediated by importin-?. Classical nuclear localization signals (cNLSs) are recognized by importin-? and are highly predictable due to their abundance of basic amino acids. However, various studies in model organisms have repeatedly demonstrated that only a fraction of nuclear proteins contain identifiable cNLSs, including those that directly interact with importin-?. Using data from the Human Protein Atlas and the Human Reference Interactome, and proteomic data from BioID/protein-proximity labeling studies using multiple human importin-? proteins, we determine that nearly 50% of the human nuclear proteome does not have a predictable cNLS. Surprisingly, between 25% and 50% of previously identified human importin-? cargoes do not have predictable cNLS. Analysis of importin-? cargo without a cNLS identified an alternative basic rich motif that does not resemble a cNLS. Furthermore, several previously suspected piggybacking proteins were identified, such as those belonging to the RNA polymerase II and transcription factor II D complexes. Additionally, many components of the mediator complex interact with at least one importin-?, yet do not have a predictable cNLS, suggesting that many of the subunits may enter the nucleus through an importin-?-dependent piggybacking mechanism.

SUBMITTER: Tessier TM

PROVIDER: S-EPMC7463951 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Piggybacking on Classical Import and Other Non-Classical Mechanisms of Nuclear Import Appear Highly Prevalent within the Human Proteome.

Tessier Tanner M TM MacNeil Katelyn M KM Mymryk Joe S JS

Biology 20200723 8

One of the most conserved cellular pathways among eukaryotes is the extensively studied classical protein nuclear import pathway mediated by importin-α. Classical nuclear localization signals (cNLSs) are recognized by importin-α and are highly predictable due to their abundance of basic amino acids. However, various studies in model organisms have repeatedly demonstrated that only a fraction of nuclear proteins contain identifiable cNLSs, including those that directly interact with importin-α. U ...[more]

PMID: 32718019

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Project description:ORF73 latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus (KSHV) is targeted to the nucleus of infected cells where it binds to chromatin and mediates viral episome persistence, interacts with cellular proteins and plays a role in latency and tumorigenesis. A structurally related LANA homolog has been identified in the retroperitoneal fibromatosis herpesvirus (RFHV), the macaque homolog of KSHV. Here, we report the evolutionary and functional conservation of a novel bi-functional nuclear localization signal (NLS) in KSHV and RFHV LANA. N-terminal peptides from both proteins were fused to EGFP or double EGFP fusions to examine their ability to induce nuclear transport of a heterologous protein. In addition, GST-pull down experiments were used to analyze the ability of LANA peptides to interact with members of the karyopherin family of nuclear transport receptors. Our studies revealed that both LANA proteins contain an N-terminal arginine/glycine (RG)-rich domain spanning a conserved chromatin-binding motif, which binds directly to importin ?1 in a RanGTP-sensitive manner and serves as an NLS in the importin ?1-mediated non-classical nuclear import pathway. Embedded within this domain is a conserved lysine/arginine-(KR)-rich bipartite motif that binds directly to multiple members of the importin ? family of nuclear import adaptors in a RanGTP-insensitive manner and serves as an NLS in the classical importin ?/?-mediated nuclear import pathway. The positioning of a classical bipartite kr-NLS embedded within a non-classical rg-NLS is a unique arrangement in these viral proteins, whose nuclear localization is critical to their functionality and to the virus life cycle. The ability to interact with multiple import receptors provides alternate pathways for nuclear localization of LANA. Since different import receptors can import cargo to distinct subnuclear compartments, a multifunctional NLS may provide LANA with an increased ability to interact with different nuclear components in its multifunctional role to maintain viral latency.

Dataset Information

Piggybacking on Classical Import and Other Non-Classical Mechanisms of Nuclear Import Appear Highly Prevalent within the Human Proteome.

Publications

Piggybacking on Classical Import and Other Non-Classical Mechanisms of Nuclear Import Appear Highly Prevalent within the Human Proteome.

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