Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, and several PTPs have been validated as therapeutic targets for human diseases. Historically, ...the development of drugs targeting PTPs has been highly challenging, leading to stigmatization of these enzymes as undruggable targets. Despite these difficulties, efforts to drug PTPs have persisted, and recent years have seen an influx of new probes providing opportunities for biological examination of old and new PTP targets. Here we discuss progress towards drugging PTPs with special emphasis on the development of selective probes with biological activity. We describe the development of new small-molecule orthosteric, allosteric, and oligomerization-inhibiting PTP inhibitors and discuss new studies targeting the receptor PTP (RPTP) subfamily with biologics.
Since their discovery at the end of the previous millennium, carbon nanotubes (CNTs) have been the object of thousands of papers describing their applications in fields ranging from physics to ...electronics, photonics, chemistry, biology, and medicine. The development of chemical approaches to modify their graphitic sidewalls enabled the generation of poly(ethylene glycol) (PEG)-modified CNTs and their exploration in multiple biomedical applications. Studies at the cellular and organism level revealed that PEG-modified CNTs have favorable pharmacokinetic and toxicology profiles. Recently, PEG-modified CNTs have been successfully tested in preclinical studies in the fields of oncology, neurology, vaccination, and imaging, suggesting that they are well suited for the generation of novel multifunctional nanodrugs. Here we will review published data about the application of PEG-modified CNTs as in vitro and in vivo therapeutic and imaging tools and describe what is known about the interaction between PEG-modified CNTs and biological systems. Although several pieces of the puzzle are still missing, we will also attempt to formulate a preliminary structure–function model for PEG-modified CNT cellular trafficking, disposition, and side effects.
PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively ...promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.
Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate ...the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell-mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell-produced cytokines.
Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Despite considerable advances in clinical treatment of RA, suboptimal response to therapy and treatment ...discontinuation are still unresolved challenges due to systemic toxicity. It is of crucial importance to actively target and deliver therapeutic agents to inflamed joints in order to promote in situ activity and decrease systemic toxicity. In this study, we found that SPARC (secreted protein acidic and rich in cysteine) was overexpressed in the synovial fluid and synovium of RA patients as well as mice with collagen-induced arthritis (CIA), which has been scarcely reported. Building upon the SPARC signature of RA joint microenvironment and the intrinsic high affinity of SPARC for albumin, we fabricated methotrexate-loaded human serum albumin nanomedicines (MTX@HSA NMs) and explored them as biomimetic drug delivery systems for RA therapy. Upon intravenous injection of chlorin e6-labeled MTX@HSA NMs into CIA mice, the fluorescence/magnetic resonance dual-modal imaging revealed higher accumulations and longer retention of MTX@HSA NMs in inflamed joints with respect to free MTX molecules. In vivo therapeutic evaluations suggested that the MTX@HSA NMs were able to attenuate the progression of RA with better efficacy and fewer side effects even at half dose of administrated MTX in comparison with free MTX. By unraveling the mechanism driving the efficient accumulation of MTX@HSA NMs in RA joints and showing their ability to improve the safety and therapeutic efficacy of MTX, our work sheds light on the development of innovative anti-RA nanomedicines with a strong potential for clinical translation.
The Contribution of PTPN22 to Rheumatic Disease Mustelin, Tomas; Bottini, Nunzio; Stanford, Stephanie M.
Arthritis & rheumatology (Hoboken, N.J.),
April 2019, Letnik:
71, Številka:
4
Journal Article
Recenzirano
Odprti dostop
One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that ...genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.
Investigation of the nanoparticle protein corona, the shell of plasma proteins formed around nanoparticles immediately after they enter the bloodstream, is a benchmark in the study of the ...applications of nanoparticles in all fields of medicine, from pharmacology to toxicology. We report the first investigation of the protein corona adsorbed onto single-walled carbon nanotubes modified with 2 kDa molecular weight polyethylene glycol chains PEG(2k)-modified SWCNTs or PEG2-SWCNTs by using a large-scale gel-based proteomics method on biological replicates. More than 240 plasma proteins were selected, and their differences were analyzed among PEG2-SWCNTs differing in surface charge and PEG conformation. The protein corona of PEG2-SWCNTs showed that coagulation proteins, immunoglobulins, apolipoproteins, and proteins of the complement system were among the proteins bound by PEG2-SWCNTs and that their recruitment was independent from the isoelectric point, molecular weight, total hydrophobicity, and number of polyaromatic residues of the proteins. Statistical analysis on protein relative abundance revealed that PEG conformation had a higher influence on the PEG2-SWCNTs’ protein corona repertoire than nanotube surface charge. PEG conformation also affected the biological performance of PEG2-SWCNTs. A change in PEG conformation from mushroom to mushroom-brush transition affected the competitive adsorption of the major constituents of the protein corona of PEG2-SWCNTs and promoted shorter blood circulation time, faster renal excretion, and higher relative spleen versus liver uptake of PEG2-SWCNTs. Our data suggest that the protein corona, along with steric stabilization, may mediate the action of PEG conformation on the pharmacokinetic profile of PEG-modified SWCNTs.
5025 Background: The acid phosphatase 1 ( ACP1) gene encodes low molecular weight protein tyrosine phosphatase (LMPTP), which is overexpressed in PCa. Previous studies demonstrate that LMPTP plays a ...critical role in PCa growth and metastasis and is evolving as a potential therapeutic target. Thus, we analyzed ACP1 expression in primary and metastatic PCa samples and the association of ACP1 with molecular profiles and clinical outcomes. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for PCa specimens (n=5028) submitted to Caris Life Sciences. ACP1-High/Low expression was defined as quartile 4 (Q4) and 1 (Q1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for samples stratified by ACP1 expression quartiles. Gene set enrichment analysis was used to assess the Hallmark collection of cancer pathways. Tumor cell PD-L1+ status (≥2+, ≥5%; SP142) was tested by immunohistochemistry. Immune cell fractions in the tumor microenvironment (TME) were estimated by RNA deconvolution using QuanTIseq. Overall survival (OS) was assessed from the time of specimen collection to death or last follow-up, with hazard ratio (HR) calculated using the Cox proportional hazards model, and P values calculated using the log-rank test. Results: Samples included 3058 (60.8%) derived from the prostate, 634 (12.6%) from lymph node metastases (LNM), and 1307 (26.0%) from distant metastases (DM). ACP1 expression was higher in LNM and DM than in the prostate (49.8 and 47.9, respectively, vs 44.1 TPM, p<0.0001 each). TP53 mutations were enriched in the highest ACP1 quartile (37.9% Q4 vs 27.0% Q1, p<0.001) among prostate samples but not LNM or DM. Pathways associated with cell cycle regulation, oxidative phosphorylation, and androgen response were enriched in Q4, while epithelial-mesenchymal transition and TNF-α signaling via NFKB pathways were enriched in Q1. Both neuroendocrine and androgen receptor signaling increased in Q4. M2 macrophages and NK cell fractions were increased, while T cells and M1 macrophages were decreased in Q4. PD-L1 expression did not differ by ACP1 expression. High ACP1 was associated with worse OS among prostate tumors (63.4 vs 86.3 months (mos) in ACP1-high vs low tumors, HR 1.5, 95% CI 1.3-1.7, p<0.0001) and DM (22.0 vs 27.7 mos in ACP1-high vs low tumors, HR 1.2, 95% CI 1.0-1.4, p<0.05) but not LNM (31.9 vs 30.9 mos in ACP1-high vs low tumors, HR 1.0, 95% CI 0.8-1.3, p=0.88). OS from the start of ARSI and taxane chemotherapy was similar in ACP1 high/low groups across prostate, LNM, and DM. Conclusions: In the largest study investigating the significance of ACP1 expression in PCa, we demonstrate that ACP1-high tumors exhibit a distinct molecular profile enriched for TP53 alterations and associated with a ‘cold’ TME. Our findings may provide a rationale for novel therapeutic targeting of ACP1-high tumors.
Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show ...that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-γ-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-γ expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-γ production, but also the protective function of iNKT cells in arthritis.
We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the
PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of ...type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.
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