Science Signaling

Journal Information
ISSN / EISSN : 1945-0877 / 1937-9145
Total articles ≅ 12,559
Current Coverage
SCOPUS
SCIE
MEDICUS
MEDLINE
PUBMED
Archived in
SHERPA/ROMEO
Filter:

Latest articles in this journal

Sarah E. Catheline, Richard D. Bell, Luke S. Oluoch, M. Nick James, Katherine Escalera-Rivera, , Martin E. Chang, Christopher Dean, Elizabeth Botto, John P. Ketz, et al.
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abf3535

Abstract:
Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase β (IKKβ) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKβ had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1β (IL-1β) in vitro, the loss of p50 enhanced the IL-1β–induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKβ activation. Overall, our data reveal that IKKβ-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.
Wei Wong
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abm4425

Abstract:
Leptin exerts its physiological effects after transcytosis in tanycytes mediated by the leptin receptor and EGFR.
, Deanne Francis, , Mark Larance, , Chris J. Novotny, , ,
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abe0161

Abstract:
Rapamycin extends maximal life span and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross-react with mTORC2. Here, we report the distinct characteristics of a third-generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Last, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila. Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin.
Annalisa M. VanHook
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abm3135

Abstract:
The bacterial bile acid metabolite isoalloLCA stimulates the differentiation of Treg cells.
Chao Wei, Shanzhi Wang, Pengwei Liu, Shou-Ting Cheng, Guoliang Qian, Shuwei Wang, Ying Fu, ,
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abi9589

Abstract:
Bacterial type IV pili (T4P) contribute to virulence and can be rapidly extended and retracted to mediate twitching motility. T4P biogenesis, which is normally limited to the cell poles, is regulated by extracellular stimuli and internal signals such as cyclic di-GMP (c-di-GMP). The c-di-GMP–binding protein FimX interacts with the T4P assembly complex and, when intracellular c-di-GMP concentrations are low, assumes a unipolar localization and promotes T4P biogenesis. Here, we demonstrated that FimX formed a complex with the two-component system consisting of the histidine kinase PdeK and its downstream response regulator PdeR. This complex promoted T4P assembly in the phytopathogen Xanthomonas oryzae pv. oryzicola and virulence in rice. PdeK and the c-di-GMP phosphodiesterase activity of PdeR were required for the unipolar localization of FimX, leading to T4P extension. High amounts of c-di-GMP reduced the affinity of FimX for PdeR in vitro, consistent with FimX promoting T4P extension only under conditions of low c-di-GMP. We propose that low intracellular amounts of c-di-GMP created by PdeR facilitate the recruitment of FimX to the leading pole of motile cells. Our findings indicate that the PdeK-PdeR two-component system connects environmental cues to second messenger turnover, resulting in a change in the intracellular concentration of c-di-GMP that promotes T4P biogenesis and virulence.
Cong Zeng, Abdul A. Waheed, Tianliang Li, , Yi-Min Zheng, Jacob S. Yount, Haitao Wen, Eric O. Freed, Shan-Lu Liu
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abc7611

Abstract:
The SERINC (serine incorporator) proteins are host restriction factors that inhibit infection by HIV through their incorporation into virions. Here, we found that SERINC3 and SERINC5 exhibited additional antiviral activities by enhancing the expression of genes encoding type I interferons (IFNs) and nuclear factor κB (NF-κB) signaling. SERINC5 interacted with the outer mitochondrial membrane protein MAVS (mitochondrial antiviral signaling) and the E3 ubiquitin ligase and adaptor protein TRAF6, resulting in MAVS aggregation and polyubiquitylation of TRAF6. Knockdown of SERINC5 in target cells increased single-round HIV-1 infectivity, as well as infection by recombinant vesicular stomatitis virus (rVSV) bearing VSV-G or Ebola virus (EBOV) glycoproteins. Infection by an endemic Asian strain of Zika virus (ZIKV), FSS13025, was also enhanced by SERINC5 knockdown, suggesting that SERINC5 has direct antiviral activities in host cells in addition to the indirect inhibition mediated by its incorporation into virions. Further experiments suggested that the antiviral activity of SERINC5 was type I IFN–dependent. Together, these results highlight a previously uncharacterized function of SERINC proteins in promoting NF-κB inflammatory signaling and type I IFN production, thus contributing to its antiviral activities.
John F. Foley
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abm2485

Abstract:
Insulin signaling in mouse adipose tissue drives the differentiation of regulatory T cells.
, Rawan Shekhani,
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abf1653

Abstract:
Heterotrimeric G proteins constitute the primary transducers of G protein–coupled receptor (GPCR) signaling. In addition to mediating ligand-induced GPCR activation, G proteins transduce basal signaling in various physiological and pathophysiological settings evoked by constitutively active, native GPCRs or disease-related receptor mutants. Optical biosensors have been developed and optimized to monitor GPCR ligand–induced activation of G proteins, but these biosensors cannot be used to detect constitutively active GPCRs. Here, we designed and validated eight bioluminescence resonance energy transfer (BRET)–based G protein sensors that can measure the activity of all four major families of G proteins. We also established a protocol to identify constitutive GPCR or G protein signaling in live cells. These G protein–based, tricistronic activity sensors (G-CASE) rely on the encoding of all three G protein subunits by a single plasmid, enabling their expression at the desired relative amounts and resulting in reduced signal variability in mammalian cells. We also present an experimental protocol to use the G-CASE sensor toolbox to quantify constitutive signaling of native and mutated GPCRs through these heterotrimeric transducers. This approach will help to characterize constitutively active GPCRs and their role in health and disease.
, Wei Yang, Meng-Ting Zhang, Li-Xia Du, Jia-He Tian, Jian-Yu Zhu, Yu Chen, Feng Hai, Shen-Bin Liu, , et al.
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abe3773

Abstract:
Morphine and other opiates are highly effective for treating moderate to severe pain. However, morphine-induced hyperalgesia and analgesic tolerance prevent durable efficacy in patients. Here, we investigated the underlying molecular mechanisms of this phenomenon. We found that repeated subcutaneous injections of morphine in mice increased the abundance of the cytokine interleukin-33 (IL-33) primarily in oligodendrocytes and astrocytes and that of its receptor ST2 mainly in astrocytes. Pharmacological inhibition or knockdown of IL-33 or ST2 in the spinal cord attenuated morphine-induced hyperalgesia and analgesic tolerance in mice, as did global knockout of either Il33 or St2, which also reduced morphine-enhanced astroglial activation and excitatory synaptic transmission. Furthermore, a pathway mediated by tumor necrosis factor receptor–associated factor 6 (TRAF6) and the kinase JNK in astrocytes was required for IL-33–mediated hyperalgesia and tolerance through promoting the production of the chemokine CXCL12 in the spinal cord. The findings suggest that targeting IL-33–ST2 signaling could enable opioids to produce sustained analgesic effects in chronic pain management.
Karsen E. Shoger, Neha Cheemalavagu, Yuqi M. Cao, Brandon A. Michalides, , Jonathan A. Cohen, ,
Science Signaling, Volume 14; https://doi.org/10.1126/scisignal.abe5137

Abstract:
Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is acutely induced by diverse cytokine stimuli in many tissues, was expressed constitutively in AMs in response to steady-state GM-CSF signaling. Cish deficiency led to the generation of foamy AMs and the accumulation of pulmonary surfactant. These phenotypic changes were associated with enhanced activation of STAT5, AKT, and ERK and increased expression of the gene encoding the transcription factor GATA2. RNA-seq analysis of Cish−/− AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Last, Cish-deficient, bone marrow–derived macrophages showed increased Gata2 expression and accumulated more lipid upon incubation with bronchoalveolar lavage fluid compared with Cish-sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and Gata2 expression to maintain AM identity and function.
Back to Top Top