Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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G protein-coupled receptors mediate neural regulation of innate immune responses in caenorhabditis elegans
Get PDFG protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that perceive many extracellular signals and transduce them into cellular physiological responses. GPCRs regulate immunity in both vertebrates and invertebrates. However, the mechanisms responsible for such regulation are not fully understood. Recent research using the genetically tractable model organism Caenorhabditis elegans has led to the identification of specific GPCRs, neurotransmitters, neurons and non-neural cells in the regulation of innate immunity. Several neural circuits have been demonstrated to function in GPCR-dependent immuno-regulatory pathways. Besides being essential in neural-immune interactions, GPCRs also regulate innate immune response in non-neural tissues cell-autonomously through mechanisms independent of neural circuits. Here we review GPCR-mediated neural control of innate immunity in C. elegans and briefly discuss GPCR-dependent immune regulation via non-neural mechanisms
An entry-competent intermediate state of the HIV-1 envelope glycoproteins
Get PDFThe human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate viral entry and are the sole target of neutralizing antibodies. Recent studies show that the metastable HIV-1 Env trimer can transit among three conformational states: State 1, State 3, and State 2, corresponding to the “closed”, “open” and intermediate conformations, respectively. During virus entry, binding to the CD4 receptor drives Env from state 1 to state 3. In the unliganded Env, transitions from the closed (State 1) conformation are restrained by intramolecular interactions among different Env residues, which regulate HIV-1 Env conformation. Releasing the specific restraints on State 1 Env leads to increased occupancy of State 2, which is a functional conformation on the entry pathway and an obligate intermediate between State 1 and State 3. Frequent sampling of intermediate State 2 allows HIV-1 to infect cells expressing low levels of CD4, and leads to resistance to several broadly neutralizing antibodies as well as small-molecule inhibitors. Recent findings provide new mechanistic insights into the function and inhibition of HIV-1 Env and will contribute to the development of new therapeutic and prophylactic interventions to combat HIV-1
HOIL1 cleavage by MALT1, the knives are out
Get PDFThe paracaspase MALT1 functions as a bifunctional regulator of lymphocyte activation following the engagement of antigen receptors. First, MALT1 scaffolds the CARMA1-BCL10-MALT1 (CBM) signaling complex in charge of activating the NF-kB transcription factor. Second, MALT1 proteolytic activity governs NF-kB fine-tuning and the homeostasis of the immune system. MALT1 is also constitutively activated in the activated B-cell like (ABC) subset of diffuse large B-cell lymphoma (DLBCL), and the discovery that its chemical inhibition is toxic has opened new perspectives of treatment. Yet, the nature of MALT1 substrates continues to be elucidated. Herein, we review the recent identification of the linear ubiquitin assembly chain complex (LUBAC) element HOIL1 as a new substrate for MALT1 in lymphocytes and lymphoma. We discuss how this processing may affect NF-kB signaling and impact on lymphocyte homeostasis
Signal transduction of Interleukin-11 and Interleukin-6 ?-Receptors
Get PDFThe cytokines Interleukin (IL)-11 and IL-6 are important mediators that regulate differentiation and proliferation of immune cells. Both cytokines bind to unique non-signaling ?-receptors (IL-11R and IL-6R, respectively), and the resulting cytokine/cytokine receptor complexes recruit a homodimer of the signal-transducing ?-receptor glycoprotein (gp)130. Gp130 is expressed ubiquitously, whereas both ?-receptors show a cell- and tissue-specific expression pattern, thus determining cellular responsiveness towards IL-6 and/or IL-11. Formation of the signaling complexes activates intracellular signaling cascades, most prominently the Janus kinase (Jak)/Signal Transducer and Activator of Transcription (STAT) pathway. In a recent paper published in Biochimie, we analyzed the signaling capacity of eight chimeric receptors consisting of different domains of IL-11R and IL-6R. Our results showed that the intracellular region, the transmembrane region or the stalk region can be swapped between the two receptors, as they are not essential to discriminate between the two cytokines. Selectivity of the two receptors is exclusively warranted by the cytokine binding module (CBM), which resides within the domains D1 to D3. These results underline a modular organization of IL-11R and IL-6R and a comparable signal transduction of both cytokines
Supersensitive odor discrimination is controlled in part by initial transient interactions between the most sensitive dorsal olfactory receptors and G-proteins
Get PDFPairs of enantiomeric odor ligands are difficult to resolve by instrumental analyses because compounds with mirror-image molecular structures have almost identical physicochemical properties. The olfactory system, however, discriminates (–)-forms of enantiomers from their (+)-forms within seconds. To investigate key olfactory receptors for enantiomer discrimination, we compared behavioral detection and discrimination thresholds of wild-type mice with those of ?D mice that lack all dorsal olfactory receptors. Surprisingly, wild-type mice displayed an exquisite “supersensitivity” to enantiomeric pairs of wine lactones and carvones in both detection and discrimination tasks using odor plume-like flows in a Y-maze. In contrast, ?D mice showed >1010-fold reductions in enantiomer discrimination sensitivity compared to wild-type mice. ?D mice detected one or both of the (–)- and (+)-enantiomers over a wide concentration range, but were unable to discriminate them. This “enantiomer odor discrimination paradox” indicates that the most sensitive dorsal receptors play a critical role in hierarchical odor coding for enantiomer identification. In addition, to identify residues responsible for the rapid and robust response of murine olfactory receptor S6 (mOR-S6) via chimeric G?15_olf, mutations of the C-terminal helix 8 were analyzed in a heterologous functional expression system. The N-terminal hydrophobic core between helix 8 and TM1?2 of mOR-S6 is important for G? activation. A point mutation of a helix 8 N-terminal acidic residue eliminated the improved response dynamics via the chimeric G?15_olf. This result suggests that an N-terminal acidic residue of helix 8 is responsible for rapid G? activation. Supersensitive odor discrimination is thus largely governed by signals from the most sensitive dorsal olfactory receptors with the shortest onset latencies, which are controlled in part by initial transient interactions between the receptor C-terminal helix 8 and the G? C-terminal region
Protein surface recognition with targeted fluorescent molecular probes
Get PDFProtein surface recognition by fluorescent molecular sensors poses an immense challenge in supramolecular recognition chemistry owing to the immense difficulty of selectively targeting these large, relatively flat and non-contiguous domains. The fact that protein surfaces can exhibit different charges, topologies, and posttranslational modifications that can be found in other proteins in the mixture is an additional factor that complicates targeting and therefore, sensing specific protein surface modifications. A recent report, however, shows that the difficulty of sensing changes that occur on the surface of specific proteins could be circumvented by attaching a relatively non-specific synthetic receptor to a specific protein binder. The latter brings the receptor near the target protein and enhances its affinity toward its surface. Modifying the synthetic receptor with an environmentally sensitive fluorescent reporter along with suitable recognition elements enables such systems to target specific regions on protein surfaces and consequently, track modifications that result from conformational changes or binding interactions
SNARE-associated proteins and receptor trafficking
Get PDFA wide variety of receptors that function on the cell surface are regulated, at least in part, through intracellular membrane trafficking including endocytosis, recycling and subsequent degradation. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) are essential molecules for the final step of intracellular membrane trafficking, i.e. fusion of transport vesicles with the target membrane. SNAREs on two opposing membranes form a trans-SNARE complex consisting of a four-helical bundle and drive a membrane fusion. The resultant cis-SNARE complex is disassembled through a process mediated by NSF and SNAPs. Cells contain families of SNAREs, and the interaction of cognate SNAREs at least contributes to the specificity of membrane fusion. The SNARE complex formation and dissociation are modulated by many SNARE-associated proteins at multiple steps including tethering, assembly and disassembly. Diverse molecular mechanisms, such as scaffolding, phosphorylation and ubiquitylation of SNARE proteins, and phosphoinositide production, are utilized for the modulation. In this review, we summarize recent progress in understanding the role of SNARE-associated proteins required for the endocytic recycling and degradation of epidermal growth factor receptor, transferrin receptor and integrins. We also discuss the physiological and pathological relevance of SNAREs and SNARE-associated proteins in the receptor trafficking
Molecular basis of shikonin-induced immunogenic cell death: insights for developing cancer therapeutics
Get PDFShikonin, a natural plant product isolated from the herb Lithospermum erythrorhizon, has been found to strongly stimulate immunogenic cell death (ICD) of tumor cells, which induced a potent immune response by dendritic cells (DCs) to suppress tumor growth and/or metastasis. Recently, specific intracellular protein targets including heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and pyruvate kinase-M2 (PKM2) have been demonstrated to act as candidate receptors for shikonin. Among them, direct binding-interference with hnRNPA1 was found to be critical for shikonin-induced immunogenicity of mammary tumor cells, which can result in strong suppression of tumor metastasis. Mechanistic studies have further revealed that specific damage-associated molecular patterns (DAMPs) associated with immunogenicity, including heat shock proteins 70 (HSP-70), calreticulin (CRT) and high mobility group box 1 (HMGB1) in tumor cell lysate (TCL), can play important and comprehensive roles in activating specific immunities of tumor cell lysate (TCL)-pulsed DCs. In this brief review article, we present these findings together and further provide a molecular mode of action as the pharmacological basis of SK-induced ICD
Major vault protein in cardiac and smooth muscle
Get PDFMajor vault protein (MVP) is the major component of the vault particle whose functions are not well understood. One proposed function of the vault is to serve as a mechanism of drug transport, which confers drug resistance in cancer cells. We show that MVP can be found in cardiac and smooth muscle. In human airway smooth muscle cells, knocking down MVP was found to cause cell death, suggesting that MVP serves as a cell survival factor. Further, our laboratory found that MVP is S-glutathionylated in response to ligand/receptor-mediated cell signaling. The S-glutathionylation of MVP appears to regulate protein-protein interactions between MVP and a protein called myosin heavy chain 9 (MYH9). Through MYH9 and Vsp34, MVP may form a complex with Beclin-1 that regulates autophagic cell death. In pulmonary vascular smooth muscle, proteasome inhibition promotes the ubiquitination of MVP, which may function as a mechanism of proteasome inhibition-mediated cell death. Investigating the functions and the regulatory mechanisms of MVP and vault particles is an exciting new area of research in cardiovascular/pulmonary pathophysiology
The antagonist SPECT tracer 123I-iododexetimide binds preferentially to the muscarinic M1 receptor in-vivo, but is it also a potential tool to assess the occupancy of muscarinic M1 receptors by agonists?
Get PDFCognitive deterioration in neuropsychiatric disorders is associated with high attrition rates giving an urgent need to develop better pharmaceutical therapies. The underlying mechanisms of cognitive impairments are unclear but research has shown that the muscarinic receptor subtype 1 (M1 receptor) plays a critical role. Blocking the M1 receptor gives rise to profound cognitive deficits, while the administration of M1 agonist drugs improves cognitive functioning. In this research highlight we will outline supporting data that the radiotracer 123I-iododexetimide preferentially binds to the M1 receptor in-vivo and can be used to assess changes in M1 receptor expression in-vivo associated with cognitive decline. These findings come from a previously published paper extensively examining binding characteristics of 123/127I-iododexetimide to muscarinic receptors. Results of biodistribution studies also has shown that acute administration of the M1/4 receptor agonist xanomeline could inhibit 127I-iododexetimide binding in M1-rich brain areas in rats, suggesting that 123I-iododexetimide may also be used to evaluate the occupancy of M1 receptors by M1 agonists in-vivo. This may be of clinical relevance considering the efficacy of M1 agonist drugs in the treatment of cognitive deficits. Here we show the results from new biodistribution experiments in rats conducted to test the hypothesis that 123I-iododexetimide may be a useful radiotracer to evaluate the M1 receptor occupancy by M1 agonists in-vivo. Contrary to our expectations, no significant change in 123I-iododexetimide ex-vivo binding was observed after acute administration of xanomeline in M1 receptor-rich brain areas, whereas significantly decreased 123I-iododexetimide binding was found after chronic treatment with xanomeline. 123I-iododexetimide single photon emission computed tomography (SPECT) may therefore be a useful imaging tool to further evaluate M1 receptor changes in neuropsychiatric disorders, as a potential stratifying biomarker, to assess the occupancy of M1 receptors after M1 antagonist treatment, or after chronic treatment with M1 agonists, although it may be less suited to evaluate the M1 receptor occupancy after acute treatment with M1 agonists. Future studies should concentrate efforts towards finding also an M1 agonist radiotracer for positron emission tomography (PET) or SPECT to assess the working mechanism of M1 agonists