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Viruses cause numerous medically important diseases, affecting developing, developed, rich and poor alike. The diseases vary in severity, including chickenpox, smallpox, influenza, shingles, herpes, rabies, polio, Ebola, hanta fever, AIDS and the common cold, amongst others. Regardless of the type of tissue or organ affected, all viruses follow the same basic steps to infect host cells. Once in contact with host cells viruses release their genetic material into the cell followed by genome replication, production of viral proteins, assembly of the virus particle and egress from the infected cell. Viruses disrupt normal host cell processes in order to facilitate their own replication/assembly by re-directing cellular machinery for viral transcription, translation, assembly, release and by inhibiting antiviral responses. Regulated nuclear transport of macromolecules through the nuclear pore complex, the only means of transport across the nuclear membrane, is essential for normal cell function and an effective antiviral response. Many viruses disrupt or exploit the nucleocytoplasmic trafficking pathways in host cells. Cytoplasmic viruses exploit the host cell nucleocytoplasmic trafficking machinery to access nuclear functions and/or disrupt nuclear transport, while several DNA viruses use the trafficking pathways to enable export of their components into the cytoplasm; yet others complete their assembly within the nucleus and use nuclear export pathways to access the cytoplasm. Indeed, the many and varied interactions of viruses and viral proteins with nucleocytoplasmic trafficking components have been invaluable in pathway discovery. Importantly, mounting evidence suggests that these interactions play essential roles in virus replication/assembly and hence may be key to understanding pathophysiology of viral diseases. This Frontiers Research Topic is dedicated to the importance of nucleocytoplasmic trafficking to viral pathogenesis.

viral nuclear interactions --- nuclear transport --- DNA Viruses --- nuclear pore complex --- RNA Viruses

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Disordered proteins are relatively recent newcomers in protein science. They were first described in detail by Wright and Dyson, in their J. Mol. Biol. paper in 1999. First, it was generally thought for more than a decade that disordered proteins or disordered parts of proteins have different amino acid compositions than folded proteins, and various prediction methods were developed based on this principle. These methods were suitable for distinguishing between the disordered (unstructured) and structured proteins known at that time. In addition, they could predict the site where a folded protein binds to the disordered part of a protein, shaping the latter into a well-defined 3D structure. Recently, however, evidence has emerged for a new type of disordered protein family whose members can undergo coupled folding and binding without the involvement of any folded proteins. Instead, they interact with each other, stabilizing their structure via “mutual synergistic folding” and, surprisingly, they exhibit the same residue composition as the folded protein. Increasingly more examples have been found where disordered proteins interact with non-protein macromolecules, adding to the already large variety of protein–protein interactions. There is also a very new phenomenon when proteins are involved in phase separation, which can represent a weak but functionally important macromolecular interaction. These phenomena are presented and discussed in the chapters of this book.

Research & information: general --- Biology, life sciences --- intrinsically disordered proteins --- epiproteome --- disordered protein platform --- molecular recognition feature --- post-translational modifications --- physiological homeostasis --- stress response --- RIN4 --- p53 --- molecular machines --- intrinsically disordered protein --- membrane-less organelle --- neurodegenerative disease --- p300 HAT acetylation --- post-translational modification --- protein aggregation --- Tau fibrillation --- intrinsically disorder proteins --- disorder-to-order regions --- protein–RNA interactions --- unstructured proteins --- conformational plasticity --- disordered protein --- folding --- ribosomal protein --- spectroscopy --- protein stability --- temperature response --- protein thermostability --- salt bridges --- meta strategy --- dual threshold --- significance voting --- decision tree based artificial neural network --- protein intrinsic disorder --- intrinsic disorder --- intrinsic disorder prediction --- intrinsically disordered region --- protein conformation --- transcriptome --- RNA sequencing --- Microarray --- differentially regulated genes --- gene ontology analysis --- functional analysis --- intrinsically disordered --- structural disorder --- correlated mutations --- co-evolution --- evolutionary couplings --- residue co-variation --- interaction surface --- residue contact network --- dehydron --- homodimer --- hydrogen bond --- inter-subunit interaction --- ion pair --- mutual synergistic folding --- solvent-accessible surface area --- stabilization center --- MLL proteins --- MLL4 --- lncRNA --- HOTAIR --- MEG3 --- leukemia --- histone lysine methyltransferase --- RNA binding --- protein --- hydration --- wide-line 1H NMR --- secretion --- immune --- extracellular --- protein-protein interaction --- structural domain --- evolution --- transcription factors --- DNA-protein interactions --- Sox2 sequential DNA loading --- smFRET --- DNA conformational landscape --- sequential DNA bending --- transcription factor dosage --- oligomer --- N-terminal prion protein --- copper binding --- prion disease mutations --- Nuclear pore complex --- FG-Nups --- phosphorylation --- coarse-grained --- CABS model --- MC simulations --- statistical force fields --- protein structure --- intrinsically disordered proteins (IDPs) --- neurodegenerative diseases --- aggregation --- drugs --- drug discovery --- plant virus --- eIF4E --- VPg --- potyvirus --- molten globule --- fluorescence anisotropy --- protein hydrodynamics

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Disordered proteins are relatively recent newcomers in protein science. They were first described in detail by Wright and Dyson, in their J. Mol. Biol. paper in 1999. First, it was generally thought for more than a decade that disordered proteins or disordered parts of proteins have different amino acid compositions than folded proteins, and various prediction methods were developed based on this principle. These methods were suitable for distinguishing between the disordered (unstructured) and structured proteins known at that time. In addition, they could predict the site where a folded protein binds to the disordered part of a protein, shaping the latter into a well-defined 3D structure. Recently, however, evidence has emerged for a new type of disordered protein family whose members can undergo coupled folding and binding without the involvement of any folded proteins. Instead, they interact with each other, stabilizing their structure via “mutual synergistic folding” and, surprisingly, they exhibit the same residue composition as the folded protein. Increasingly more examples have been found where disordered proteins interact with non-protein macromolecules, adding to the already large variety of protein–protein interactions. There is also a very new phenomenon when proteins are involved in phase separation, which can represent a weak but functionally important macromolecular interaction. These phenomena are presented and discussed in the chapters of this book.

Research & information: general --- Biology, life sciences --- intrinsically disordered proteins --- epiproteome --- disordered protein platform --- molecular recognition feature --- post-translational modifications --- physiological homeostasis --- stress response --- RIN4 --- p53 --- molecular machines --- intrinsically disordered protein --- membrane-less organelle --- neurodegenerative disease --- p300 HAT acetylation --- post-translational modification --- protein aggregation --- Tau fibrillation --- intrinsically disorder proteins --- disorder-to-order regions --- protein–RNA interactions --- unstructured proteins --- conformational plasticity --- disordered protein --- folding --- ribosomal protein --- spectroscopy --- protein stability --- temperature response --- protein thermostability --- salt bridges --- meta strategy --- dual threshold --- significance voting --- decision tree based artificial neural network --- protein intrinsic disorder --- intrinsic disorder --- intrinsic disorder prediction --- intrinsically disordered region --- protein conformation --- transcriptome --- RNA sequencing --- Microarray --- differentially regulated genes --- gene ontology analysis --- functional analysis --- intrinsically disordered --- structural disorder --- correlated mutations --- co-evolution --- evolutionary couplings --- residue co-variation --- interaction surface --- residue contact network --- dehydron --- homodimer --- hydrogen bond --- inter-subunit interaction --- ion pair --- mutual synergistic folding --- solvent-accessible surface area --- stabilization center --- MLL proteins --- MLL4 --- lncRNA --- HOTAIR --- MEG3 --- leukemia --- histone lysine methyltransferase --- RNA binding --- protein --- hydration --- wide-line 1H NMR --- secretion --- immune --- extracellular --- protein-protein interaction --- structural domain --- evolution --- transcription factors --- DNA-protein interactions --- Sox2 sequential DNA loading --- smFRET --- DNA conformational landscape --- sequential DNA bending --- transcription factor dosage --- oligomer --- N-terminal prion protein --- copper binding --- prion disease mutations --- Nuclear pore complex --- FG-Nups --- phosphorylation --- coarse-grained --- CABS model --- MC simulations --- statistical force fields --- protein structure --- intrinsically disordered proteins (IDPs) --- neurodegenerative diseases --- aggregation --- drugs --- drug discovery --- plant virus --- eIF4E --- VPg --- potyvirus --- molten globule --- fluorescence anisotropy --- protein hydrodynamics --- intrinsically disordered proteins --- epiproteome --- disordered protein platform --- molecular recognition feature --- post-translational modifications --- physiological homeostasis --- stress response --- RIN4 --- p53 --- molecular machines --- intrinsically disordered protein --- membrane-less organelle --- neurodegenerative disease --- p300 HAT acetylation --- post-translational modification --- protein aggregation --- Tau fibrillation --- intrinsically disorder proteins --- disorder-to-order regions --- protein–RNA interactions --- unstructured proteins --- conformational plasticity --- disordered protein --- folding --- ribosomal protein --- spectroscopy --- protein stability --- temperature response --- protein thermostability --- salt bridges --- meta strategy --- dual threshold --- significance voting --- decision tree based artificial neural network --- protein intrinsic disorder --- intrinsic disorder --- intrinsic disorder prediction --- intrinsically disordered region --- protein conformation --- transcriptome --- RNA sequencing --- Microarray --- differentially regulated genes --- gene ontology analysis --- functional analysis --- intrinsically disordered --- structural disorder --- correlated mutations --- co-evolution --- evolutionary couplings --- residue co-variation --- interaction surface --- residue contact network --- dehydron --- homodimer --- hydrogen bond --- inter-subunit interaction --- ion pair --- mutual synergistic folding --- solvent-accessible surface area --- stabilization center --- MLL proteins --- MLL4 --- lncRNA --- HOTAIR --- MEG3 --- leukemia --- histone lysine methyltransferase --- RNA binding --- protein --- hydration --- wide-line 1H NMR --- secretion --- immune --- extracellular --- protein-protein interaction --- structural domain --- evolution --- transcription factors --- DNA-protein interactions --- Sox2 sequential DNA loading --- smFRET --- DNA conformational landscape --- sequential DNA bending --- transcription factor dosage --- oligomer --- N-terminal prion protein --- copper binding --- prion disease mutations --- Nuclear pore complex --- FG-Nups --- phosphorylation --- coarse-grained --- CABS model --- MC simulations --- statistical force fields --- protein structure --- intrinsically disordered proteins (IDPs) --- neurodegenerative diseases --- aggregation --- drugs --- drug discovery --- plant virus --- eIF4E --- VPg --- potyvirus --- molten globule --- fluorescence anisotropy --- protein hydrodynamics

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Every minute, 34 new patients are diagnosed with cancer globally. Although over the past 50 years treatments have improved and survival rates have increased dramatically for several types of cancers, many remain incurable. Several aggressive types of blood and solid cancers form when mutations occur in a critical cellular signaling pathway, the JAK-STAT pathway; (Janus Kinase-Signal Transducer and Activator of Transcription). Currently, there are no clinically available drugs that target the oncogenic STAT3/5 proteins in particular or their Gain of Function hyperactive mutant products. Here, we summarize targeting approaches on STAT3/5, as the field moves towards clinical applications as well as we illuminate on upstream or downstream JAK-STAT pathway interference with kinase inhibitors, heat shock protein blockers or changing nuclear import/export processes. We cover the design paradigms and medicinal chemistry approaches to illuminate progress and challenges in understanding the pleiotropic role of STAT3 and STAT5 in oncogenesis, the microenvironment, the immune system in particular, all culminating in a complex interplay towards cancer progression.

multiple myeloma --- STAT3 --- S3I-1757 --- nanoparticle --- CD38 --- siRNA/RNAi --- polyethylenimine --- PEI --- lipopolyplex --- siRNA delivery --- glioma --- glioblastoma --- STAT5 --- AKT --- ERK1/2 --- prolactin --- androgens --- prostate cancer --- knockout --- escape mechanisms --- stem/progenitor cells --- cell hierarchy --- cancer --- CD4+ T cells --- CD8+ T cells --- myeloid cells --- immune check point --- hepatitis C virus (HCV) --- cirrhosis --- hepatocellular carcinoma (HCC) --- endoplasmic reticulum (ER) stress --- oxidative stress (OS) --- unfolded protein response (UPR) --- microRNA-122 (miR-122) --- nuclear factor erythroid 2-related factor 2 (NRF2) --- signal transducer and activator of transcription 3 (STAT3) --- hepatocyte nuclear factor 4 alpha (HNF4A) --- solid cancers --- cell cycle --- apoptosis --- inflammation --- mitochondria --- stemness --- tumor suppression --- melanoma --- autoimmune disease --- immunotherapy --- tumor–immune cell interactions --- breast cancer --- PD-L1 --- M2 macrophages --- NK cells --- STAT3 inhibitor XIII --- hedging --- transaction costs --- dynamic programming --- risk management --- post-decision state variable --- cancer progression --- cancer-stem cell --- cytokine --- therapy resistance --- metastasis --- immunosuppression --- tumor microenvironment --- proliferation --- tyrosine kinase 2 --- JAK family of protein tyrosine kinases --- signal transducer and activator of transcription --- cytokine receptor signaling --- gain-of-function mutation --- tumorigenesis --- ADAM17 --- interleukin-6 --- trans-signaling --- epidermal growth factor receptor (EGF-R) --- shedding --- metalloprotease --- tumor necrosis factor alpha (TNFα) --- inflammation associated cancer --- colon cancer --- lung cancer --- SH2 domain --- mutations --- autosomal-dominant hyper IgE syndrome --- inflammatory hepatocellular adenomas --- T-cell large granular lymphocytic leukemia --- T-cell prolymphocytic leukemia --- growth hormone insensitivity syndrome --- nuclear pore complex --- nuclear transport receptors --- nucleocytoplasmic shuttling --- targeting --- tumor-associated macrophages --- adoptive T cell therapy --- immune suppression --- STAT transcription factors --- JAK --- STAT --- T-PLL --- T-cell leukemia --- meta-analysis --- STAT5B signaling --- small-molecule inhibitors --- cancer models --- companion animals --- comparative oncology --- pharmacological inhibitor --- STAT5 signaling --- chemotherapy resistance --- myeloid leukemia --- heat shock proteins --- chaperones --- stabilization --- targeted therapy --- ovarian cancer --- hematopoietic cancers --- therapeutic targeting --- pharmacological inhibitors --- mTOR --- Bone Marrow Failure Syndromes --- lymphocytes --- lymphoma --- T-cells --- RHOA --- NGS --- MPN --- JAK2 V617F --- neoplastic stem cells --- n/a --- tumor-immune cell interactions