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Frontiers in Immunology 2020C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event... (Review)
Review
C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.
Topics: C-Reactive Protein; Disease Progression; Humans; Inflammation; Protein Conformation; Protein Isoforms
PubMed: 33013897
DOI: 10.3389/fimmu.2020.02126 -
Cell Reports May 2023Response to multiple microenvironmental cues and resilience to mechanical stress are essential features of trafficking leukocytes. Here, we describe unexpected role of...
Response to multiple microenvironmental cues and resilience to mechanical stress are essential features of trafficking leukocytes. Here, we describe unexpected role of titin (TTN), the largest protein encoded by the human genome, in the regulation of mechanisms of lymphocyte trafficking. Human T and B lymphocytes express five TTN isoforms, exhibiting cell-specific expression, distinct localization to plasma membrane microdomains, and different distribution to cytosolic versus nuclear compartments. In T lymphocytes, the LTTN1 isoform governs the morphogenesis of plasma membrane microvilli independently of ERM protein phosphorylation status, thus allowing selectin-mediated capturing and rolling adhesions. Likewise, LTTN1 controls chemokine-triggered integrin activation. Accordingly, LTTN1 mediates rho and rap small GTPases activation, but not actin polymerization. In contrast, chemotaxis is facilitated by LTTN1 degradation. Finally, LTTN1 controls resilience to passive cell deformation and ensures T lymphocyte survival in the blood stream. LTTN1 is, thus, a critical and versatile housekeeping regulator of T lymphocyte trafficking.
Topics: Humans; T-Lymphocytes; Connectin; Cell Adhesion; Signal Transduction; Protein Isoforms; Lymphocyte Activation
PubMed: 37204926
DOI: 10.1016/j.celrep.2023.112516 -
Seminars in Cell & Developmental Biology Jun 2020Actin is one of the most abundant and essential intracellular proteins that mediates nearly every form of cellular movement and underlies such key processes as... (Review)
Review
Actin is one of the most abundant and essential intracellular proteins that mediates nearly every form of cellular movement and underlies such key processes as embryogenesis, tissue integrity, cell division and contractility of all types of muscle and non-muscle cells. In mammals, actin is represented by six isoforms, which are encoded by different genes but produce proteins that are 95-99 % identical to each other. The six actin genes have vastly different functions in vivo, and the small amino acid differences between the proteins they encode are rigorously maintained through evolution, but the underlying differences behind this distinction, as well as the importance of specific amino acid sequences for each actin isoform, are not well understood. This review summarizes different levels of actin isoform-specific regulation in cellular and developmental processes, starting with the nuclear actin's role in transcription, and covering the gene-level, mRNA-level, and protein-level regulation, with a special focus on mammalian actins in non-muscle cells.
Topics: Actins; Animals; Cells; Growth and Development; Humans; Protein Isoforms
PubMed: 32001148
DOI: 10.1016/j.semcdb.2019.12.003 -
Angewandte Chemie (International Ed. in... May 2021The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins...
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N-terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan-inhibition of all four Hsp90 isoforms. Therefore, the development of isoform-selective Hsp90 inhibitors is sought to delineate the pathological role played by each isoform. Herein, we describe a structure-based approach that was used to design the first Hsp90α-selective inhibitors, which exhibit >50-fold selectivity versus other Hsp90 isoforms.
Topics: Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Protein Isoforms
PubMed: 33621416
DOI: 10.1002/anie.202015422 -
BMB Reports Jul 2021Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect... (Review)
Review
Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs. [BMB Reports 2021; 54(7): 335-343].
Topics: Alternative Splicing; Asymmetric Cell Division; Carcinogenesis; Cell Division; Cell Line, Tumor; Cell Lineage; Cell Proliferation; Humans; Membrane Proteins; Neoplastic Stem Cells; Nerve Tissue Proteins; Protein Isoforms; Receptors, Notch; Tumor Suppressor Protein p53
PubMed: 34078527
DOI: 10.5483/BMBRep.2021.54.7.048 -
Scientific Reports Sep 2020The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein...
The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein isoforms have been described, which have different immunosuppressive potentials. HLA-F has three transcript variants, resulting in three different protein isoforms. The aim of this study was to evaluate the prognostic and predictive value of HLA-G and HLA-F protein isoform expression patterns in patients with breast cancer. Core biopsies were taken at diagnosis in patients with HER2+ (n = 28), luminal B-like (n = 49) and triple-negative (n = 38) breast cancers who received neoadjuvant chemotherapy. Expression levels of HLA-F and -G were correlated with the pathological complete response (pCR). Protein expression was determined by Western blot analysis, using two antibodies for each HLA, specific for different isoforms. The protein expression of HLA isoforms did not significantly differ between breast cancer subtypes. However, some initial indications were found for an association between the soluble HLA-G6 protein isoform and pCR in HER2+ breast cancer. The study provides preliminary evidence for the evaluation of HLA-G isoform expression, in particular HLA-G6, as a possible new marker for pCR in HER2+ breast cancer.
Topics: Adult; Aged; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; HLA-G Antigens; Histocompatibility Antigens Class I; Humans; Middle Aged; Neoadjuvant Therapy; Prognosis; Prospective Studies; Protein Isoforms; Receptor, ErbB-2; Treatment Outcome
PubMed: 32978482
DOI: 10.1038/s41598-020-72837-3 -
Scientific Reports Jun 2022Sepsis is caused by an uncontrolled inflammatory response, whose underlying mechanisms are not fully understood. It is well known that the majority of human genes can be...
Sepsis is caused by an uncontrolled inflammatory response, whose underlying mechanisms are not fully understood. It is well known that the majority of human genes can be expressed as alternative isoforms. While isoform switching is implicated in many diseases and is particularly prominent in cancer, it has never been reported in the context of sepsis. Patients presented to the emergency department of three tertiary care hospitals from January 2020 to December 2020 were enrolled. Clinical variables and genome-wide transcriptome of peripheral blood mononuclear cells (PBMC) were obtained. Isoform switching analysis were performed to identify significant isoform switches and relevant biological consequences. A total of 48 subjects with sepsis, involving 42 survivors and 6 non-survivors, admitted to the emergency department of three tertiary care hospitals were enrolled in this study. PBMCs were extracted for RNA sequencing (RNA-seq). Patients (n = 4) with mild stroke or acute coronary syndrome without infection were enrolled in this study as controls. The most frequent functional changes resulting from isoform switching were changes affecting the open reading frame, protein domains and intron retention. Many genes without differences in gene expression showed significant isoform switching. Many genes with significant isoform switches ([Formula: see text]> 0.1) were associated with higher mortality risk, including PIGS, CASP3, LITAF, HBB and RUVBL2. The study for the first time described the landscape of isoform switching in sepsis, including differentially expressed isoform fractions between patients with and without sepsis and survivors and nonsurvivors. The biological consequences of isoform switching, including protein domain loss, signal peptide gain, and intron retention, were identified.
Topics: ATPases Associated with Diverse Cellular Activities; Carrier Proteins; Cohort Studies; DNA Helicases; Gene Expression Profiling; Humans; Leukocytes, Mononuclear; Protein Isoforms; Sepsis
PubMed: 35715539
DOI: 10.1038/s41598-022-14231-9 -
Life Science Alliance Oct 2023Non-small cell lung cancer (NSCLC) is the main subtype of lung cancer. The role of hPCL3 isoforms, hPCL3S and hPCL3L, remains ambiguous. This study examines the...
Non-small cell lung cancer (NSCLC) is the main subtype of lung cancer. The role of hPCL3 isoforms, hPCL3S and hPCL3L, remains ambiguous. This study examines the functional implications of these isoforms in NSCLC, using lung cancer cell lines A549 and NCI-H226c for in vivo and in vitro analyses. The results indicate that elevated expression of both hPCL3S and hPCL3L correlates with diminished overall survival, although only hPCL3S levels are augmented in clinical NSCLC specimens. Inhibition of either isoform leads to reduced cell proliferation, invasion, and migration, with hPCL3S knockdown displaying superior effectiveness. Moreover, the findings reveal that TRIM21 interacts with both isoforms and mediates hPCL3S degradation through K48-linked ubiquitination in NSCLC cells. Conversely, TRIM21 does not facilitate hPCL3L degradation, despite forming K63-linked polyubiquitin chains. These observations highlight the divergent roles of hPCL3 isoforms in NSCLC and underscore the potential therapeutic value of targeting hPCL3S.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Lung Neoplasms; Protein Isoforms; Ubiquitination
PubMed: 37507137
DOI: 10.26508/lsa.202302060 -
The Journal of Biological Chemistry Jun 2023Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in...
Identifying events that regulate the prenylation and localization of small GTPases will help define new strategies for therapeutic targeting of these proteins in disorders such as cancer, cardiovascular disease, and neurological deficits. Splice variants of the chaperone protein SmgGDS (encoded by RAP1GDS1) are known to regulate prenylation and trafficking of small GTPases. The SmgGDS-607 splice variant regulates prenylation by binding preprenylated small GTPases but the effects of SmgGDS binding to the small GTPase RAC1 versus the splice variant RAC1B are not well defined. Here we report unexpected differences in the prenylation and localization of RAC1 and RAC1B and their binding to SmgGDS. Compared to RAC1, RAC1B more stably associates with SmgGDS-607, is less prenylated, and accumulates more in the nucleus. We show that the small GTPase DIRAS1 inhibits binding of RAC1 and RAC1B to SmgGDS and reduces their prenylation. These results suggest that prenylation of RAC1 and RAC1B is facilitated by binding to SmgGDS-607 but the greater retention of RAC1B by SmgGDS-607 slows RAC1B prenylation. We show that inhibiting RAC1 prenylation by mutating the CAAX motif promotes RAC1 nuclear accumulation, suggesting that differences in prenylation contribute to the different nuclear localization of RAC1 versus RAC1B. Finally, we demonstrate RAC1 and RAC1B that cannot be prenylated bind GTP in cells, indicating that prenylation is not a prerequisite for activation. We report differential expression of RAC1 and RAC1B transcripts in tissues, consistent with these two splice variants having unique functions that might arise in part from their differences in prenylation and localization.
Topics: Protein Isoforms; Prenylation; Monomeric GTP-Binding Proteins; rac1 GTP-Binding Protein; Protein Prenylation
PubMed: 37059183
DOI: 10.1016/j.jbc.2023.104698 -
Translational Psychiatry Nov 2023Neurexins are synaptic adhesion molecules that play diverse roles in synaptic development, function, maintenance, and plasticity. Neurexin genes have been associated...
Neurexins are synaptic adhesion molecules that play diverse roles in synaptic development, function, maintenance, and plasticity. Neurexin genes have been associated with changes in human behavior, where variants in NRXN1 are associated with autism, schizophrenia, and Tourette syndrome. While NRXN1, NRXN2, and NRXN3 all encode major α and β isoforms, NRXN1 uniquely encodes a γ isoform, for which mechanistic roles in behavior have yet to be defined. Here, we show that both α and γ isoforms of neurexin/nrx-1 are required for the C. elegans behavioral response to food deprivation, a sustained period of hyperactivity upon food loss. We find that the γ isoform regulates initiation and the α isoform regulates maintenance of the behavioral response to food deprivation, demonstrating cooperative function of multiple nrx-1 isoforms in regulating a sustained behavior. The γ isoform alters monoamine signaling via octopamine, relies on specific expression of NRX-1 isoforms throughout the relevant circuit, and is independent of neuroligin/nlg-1, the canonical trans-synaptic partner of nrx-1. The α isoform regulates the pre-synaptic structure of the octopamine producing RIC neuron and its maintenance role is conditional on neuroligin/nlg-1. Collectively, these results demonstrate that neurexin isoforms can have separate behavioral roles and act cooperatively across neuronal circuits to modify behavior, highlighting the need to directly analyze and consider all isoforms when defining the contribution of neurexins to behavior.
Topics: Animals; Humans; Caenorhabditis elegans; Octopamine; Cell Adhesion Molecules, Neuronal; Protein Isoforms; Neurons; Synapses; Caenorhabditis elegans Proteins
PubMed: 38036526
DOI: 10.1038/s41398-023-02668-z