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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.

Project description:Background and objectiveTo determine the population prevalence and associated health impairment of disorders of gut-brain interaction (DGBI) across Great Britain, and the emphasis placed upon them within medical education.MethodsAn Internet-based cross-sectional health survey was completed by 1906 general population adults across Great Britain without self-reported organic GI disease. The survey enquired for demographics, symptom-based criteria for Rome IV DGBI, healthcare use, non-GI somatic symptoms, and quality of life. As a separate analysis, we evaluated which DGBI are considered core knowledge at undergraduate medical school level and post-graduate specialization level for Gastroenterologists and General Practitioners.ResultsThe overall prevalence of DGBI across Great Britain was 37%, being similar for England (37%), Scotland (33%), and Wales (36%); p = 0.66. There was no difference between English regions (range 33%-43%, p = 0.26). The prevalence of DGBI was highest in those aged 18-40 years (40%), then 40-64 years (37%), and least amongst those ≥65 years (29%); p < 0.001. The most common DGBI were bowel disorders (30%), followed by gastroduodenal (10.5%), anorectal (8.1%) and oesophageal disorders (6.2%). Individuals with DGBI were significantly more likely than those without DGBI to have increased GI-related healthcare visits, medication use, surgical interventions, non-GI somatic symptoms, and reduced quality of life. One-in-three people with DGBI had multiple GI organ regions involved and this correlated with increased health impairment (p < 0.001). The only DGBI mentioned across all medical training curricula is irritable bowel syndrome, while the General Practitioner and Gastroenterology Curricula also recognise the outdated term non-ulcer dyspepsia (as opposed to functional dyspepsia). The 2010 Gastroenterology Curriculum also includes functional constipation and disordered defecation, with the incoming 2022 iteration adding in functional upper GI syndromes, functional abdominal pain, and opioid-induced GI disturbances.ConclusionDisorders of gut-brain interaction are common across Great Britain and incur substantial health impairment. However, they are generally under-taught within the British medical education system. Increasing awareness and education of disorders of gut-brain interaction might improve patient outcomes.

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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