scholarly journals Signal Inhibitory Receptor on Leukocytes-1 recognizes S100 proteins

2021 ◽  
Author(s):  
Matevž Rumpret ◽  
Helen J. von Richthofen ◽  
Maarten van der Linden ◽  
Geertje H. A. Westerlaken ◽  
Cami Talavera Ormeño ◽  
...  
Keyword(s):  
Calcium Binding ◽  
S100 Protein ◽  
S100 Proteins ◽  
Human Neutrophils ◽  
Ros Production ◽  
Inhibitory Receptor ◽  
Binding Domains ◽  
Activating Receptors ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. We here identify S100 proteins as SIRL-1 ligands. S100 proteins are composed of two calcium-binding domains. Various S100 proteins are damage-associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL-1 recognizes individual calcium-binding domains of all tested S100 proteins. Blocking SIRL-1 on human neutrophils enhanced S100 protein S100A6-induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL-1. We conclude that SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs.

S100A13 and S100A6 exhibit distinct translocation pathways in endothelial cells

2002 ◽  
Vol 115 (15) ◽  
pp. 3149-3158 ◽  
Author(s):  
Hsiao-Ling Hsieh ◽  
Beat W. Schäfer ◽  
Jos A. Cox ◽  
Claus W. Heizmann
Keyword(s):  
Endothelial Cells ◽  
Calcium Binding ◽  
Protein Translocation ◽  
S100 Proteins ◽  
Cellular Functions ◽  
Specific Expression ◽  
Binding Domains ◽  
Cellular Environment ◽  
Ef Hands ◽  
Physiological Tasks

S100 proteins have attracted great interest in recent years because of their cell- and tissue-specific expression and association with various human pathologies. Most S100 proteins are small acidic proteins with calcium-binding domains — the EF hands. It is thought that this group of proteins carry out their cellular functions by interacting with specific target proteins, an interaction that is mainly dependent on exposure of hydrophobic patches, which result from calcium binding. S100A13, one of the most recently identified members of the S100 family, is expressed in various tissues. Interestingly,hydrophobic exposure was not observed upon calcium binding to S100A13 even though the dimeric form displays two high- and two low- affinity sites for calcium. Here, we followed the translocation of S100A13 in response to an increase in intracellular calcium levels, as protein translocation has been implicated in assembly of signaling complexes and signaling cascades, and several other S100 proteins are involved in such events. Translocation of S100A13 was observed in endothelial cells in response to angiotensin II, and the process was dependent on the classic Golgi-ER pathway. By contrast, S100A6 translocation was found to be distinct and dependent on actin-stress fibers. These experiments suggest that different S100 proteins utilize distinct translocation pathways, which might lead them to certain subcellular compartments in order to perform their physiological tasks in the same cellular environment.

scholarly journals S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Yu Wu ◽  
Qi Zhou ◽  
Fangyue Guo ◽  
Mingming Chen ◽  
Xufeng Tao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Current Knowledge ◽  
S100 Protein ◽  
Structural Similarity ◽  
Enzyme Activation ◽  
S100 Proteins ◽  
Effective Interventions ◽  
Vital Functions

Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.

scholarly journals Calcium-dependent and -independent interactions of the S100 protein family

2006 ◽  
Vol 396 (2) ◽  
pp. 201-214 ◽  
Author(s):  
Liliana Santamaria-Kisiel ◽  
Anne C. Rintala-Dempsey ◽  
Gary S. Shaw
Keyword(s):  
Protein Interactions ◽  
Calcium Binding ◽  
S100 Protein ◽  
Cytoskeletal Proteins ◽  
S100 Proteins ◽  
Target Proteins ◽  
Calcium Dependent ◽  
Ef Hand

The S100 proteins comprise at least 25 members, forming the largest group of EF-hand signalling proteins in humans. Although the proteins are expressed in many tissues, each S100 protein has generally been shown to have a preference for expression in one particular tissue or cell type. Three-dimensional structures of several S100 family members have shown that the proteins assume a dimeric structure consisting of two EF-hand motifs per monomer. Calcium binding to these S100 proteins, with the exception of S100A10, results in an approx. 40° alteration in the position of helix III, exposing a broad hydrophobic surface that enables the S100 proteins to interact with a variety of target proteins. More than 90 potential target proteins have been documented for the S100 proteins, including the cytoskeletal proteins tubulin, glial fibrillary acidic protein and F-actin, which have been identified mostly from in vitro experiments. In the last 5 years, efforts have concentrated on quantifying the protein interactions of the S100 proteins, identifying in vivo protein partners and understanding the molecular specificity for target protein interactions. Furthermore, the S100 proteins are the only EF-hand proteins that are known to form both homo- and hetero-dimers, and efforts are underway to determine the stabilities of these complexes and structural rationales for their formation and potential differences in their biological roles. This review highlights both the calcium-dependent and -independent interactions of the S100 proteins, with a focus on the structures of the complexes, differences and similarities in the strengths of the interactions, and preferences for homo- compared with hetero-dimeric S100 protein assembly.

scholarly journals Recognition of S100 proteins by Signal Inhibitory Receptor on Leukocytes‐1 negatively regulates human neutrophils

2021 ◽  
Author(s):  
Matevž Rumpret ◽  
Helen J. Richthofen ◽  
Maarten van der Linden ◽  
Geertje H. A. Westerlaken ◽  
Cami Talavera Ormeño ◽  
...  
Keyword(s):  
S100 Proteins ◽  
Human Neutrophils ◽  
Inhibitory Receptor

scholarly journals Isolation of the murine S100 protein MRP14 (14 kDa migration-inhibitory-factor-related protein) from activated spleen cells: characterization of post-translational modifications and zinc binding

1996 ◽  
Vol 316 (1) ◽  
pp. 285-293 ◽  
Author(s):  
Mark J. RAFTERY ◽  
Craig A. HARRISON ◽  
Paul ALEWOOD ◽  
Alun JONES ◽  
Carolyn L. GECZY
Keyword(s):  
Concanavalin A ◽  
Migration Inhibitory Factor ◽  
Calcium Binding ◽  
S100 Protein ◽  
Inhibitory Factor ◽  
High Yield ◽  
Human Neutrophils ◽  
Related Protein ◽  
Spleen Cells ◽  
Post Translational Modifications

MRP14 (macrophage migration-inhibitory factor-related protein of molecular mass 14 kDa) is an S100 calcium binding protein constitutively expressed in human neutrophils which may be associated with cellular activation/inflammation. Murine MRP14 expression was up-regulated following concanavalin A activation of spleen cells, and the protein was isolated from conditioned medium in high yield (approx. 500 ng/ml). MRP14 had a mass of 12972±2 Da by electrospray ionization MS, whereas the theoretical mass derived from the cDNA sequence, after removal of the initiator Met, was 12918 Da, suggesting that the protein was post-translationally modified. We identified four post-translational modifications of MRP14: removal of the N-terminal Met, N-terminal acetylation, disulphide bond formation between Cys79 and Cys90, and 1-methylation of His106; the calculated mass was then 12971.8 Da. Methylation of His106 was further characterized after incubation of spleen cells with L-[methyl-3H]Met during concanavalin A stimulation. Sequential analysis of a peptide (obtained by digestion with Lys C) containing methylated His indicated that > 80% of the label in the cycle corresponded to His106, suggesting that the methyl residue was transferred from S-adenosyl-L-methionine. Comparison of the C18 reverse-phase HPLC retention times of phenylthiocarbamoyl derivatives of a hydrolysed digest peptide of MRP14 with those of standards confirmed methyl substitution on the 1-position of the imidazole ring. MRP14 bound more 65Zn2+ than the same amounts of the 10 kDa chemotactic protein (CP10) or S100β. Ca2+ decreased Zn2+ binding in S100β but it did not influence binding to MRP14, suggesting that the Zn2+ binding site was distinct from and independent of the two Ca2+ binding domains.

scholarly journals Release mechanisms of major DAMPs

APOPTOSIS ◽  
2021 ◽  
Vol 26 (3-4) ◽  
pp. 152-162
Author(s):  
Atsushi Murao ◽  
Monowar Aziz ◽  
Haichao Wang ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Rna Binding ◽  
High Mobility ◽  
Live Cells ◽  
Membrane Channel ◽  
Membrane Rupture ◽  
Underlying Mechanisms ◽  
Shock Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Secretory Lysosomes

AbstractDamage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus, therapeutically targeting DAMPs has potential to provide novel and effective treatments. When establishing anti-DAMP strategies, it is important not only to focus on the DAMPs as inflammatory mediators but also to take into account the underlying mechanisms of their release from cells and tissues. DAMPs can be released passively by membrane rupture due to necrosis/necroptosis, although the mechanisms of release appear to differ between the DAMPs. Other types of cell death, such as apoptosis, pyroptosis, ferroptosis and NETosis, can also contribute to DAMP release. In addition, some DAMPs can be exported actively from live cells by exocytosis of secretory lysosomes or exosomes, ectosomes, and activation of cell membrane channel pores. Here we review the shared and DAMP-specific mechanisms reported in the literature for high mobility group box 1, ATP, extracellular cold-inducible RNA-binding protein, histones, heat shock proteins, extracellular RNAs and cell-free DNA.

scholarly journals Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kiran Todkar ◽  
Lilia Chikhi ◽  
Véronique Desjardins ◽  
Firas El-Mortada ◽  
Geneviève Pépin ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mitochondrial Proteins ◽  
Control Mechanisms ◽  
Mitochondrial Content ◽  
Sorting Nexin ◽  
Inflammatory Conditions ◽  
Selective Targeting ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Insight Into

AbstractMost cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

scholarly journals Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2566
Author(s):  
María Julia Lamberti ◽  
Annunziata Nigro ◽  
Vincenzo Casolaro ◽  
Natalia Belén Rumie Vittar ◽  
Jessica Dal Col
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Current Status ◽  
Immunogenic Cell Death ◽  
Basal Expression ◽  
Antigen Presenting ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

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