Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. ...However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H
+
-ATPase. Notably, executive mechanisms of both TRAIL- and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38α increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF- and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches.
Female signals of fertility have evolved in diverse taxa. Among the most interesting study systems are those of multimale multifemale group-living primates, where females signal fertility to males ...through multiple signals, and in which there is substantial inter-specific variation in the composition and reliability of such signals. Among the macaques, some species display reliable behavioural and/or anogenital signals while others do not. One cause of this variation may be differences in male competitive regimes: some species show marked sexual dimorphism and reproductive skew, with males fighting for dominance, while others show low dimorphism and skew, with males queuing for dominance. As such, there is variation in the extent to which rank is a reliable proxy for male competitiveness, which may affect the extent to which it is in females' interest to signal ovulation reliably. However, data on ovulatory signals are absent from species at one end of the macaque continuum, where selection has led to high sexual dimorphism and male reproductive skew. Here we present data from 31 cycles of 19 wild female crested macaques, a highly sexually dimorphic species with strong mating skew. We collected measures of ovarian hormone data from faeces, sexual swelling size from digital images, and male and female behaviour.
We show that both sexual swelling size and female proceptivity are graded-signals, but relatively reliable indicators of ovulation, with swelling size largest and female proceptive behaviours most frequent around ovulation. Sexual swelling size was also larger in conceptive cycles. Male mating behaviour was well timed to female ovulation, suggesting that males had accurate information about this.
Though probabilistic, crested macaque ovulatory signals are relatively reliable. We argue that in species where males fight over dominance, male dominance rank is surrogate for competitiveness. Under these circumstances it is in the interest of females to increase paternity concentration and assurance in dominants beyond levels seen in species where such competition is less marked. As such, we suggest that it may in part be variation in male competitive regimes that leads to the evolution of fertility signalling systems of different reliability.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Binding of tumor necrosis factor (TNF) to TNF-receptor 1 (TNF-R1) can induce either cell survival or cell death. The selection between these diametrically opposed effects depends on the subcellular ...location of TNF-R1: plasma membrane retention leads to survival, while endocytosis leads to cell death. How the respective TNF-R1 associated signaling complexes are recruited to the distinct subcellular location is not known. Here, we identify palmitoylation of TNF-R1 as a molecular mechanism to achieve signal diversification.
Human monocytic U937 cells were analyzed. Palmitoylated proteins were enriched by acyl resin assisted capture (AcylRAC) and analyzed by western blot and mass spectrometry. Palmitoylation of TNF-R1 was validated by metabolic labeling. TNF induced depalmitoylation and involvement of APT2 was analyzed by enzyme activity assays, pharmacological inhibition and shRNA mediated knock-down. TNF-R1 palmitoylation site analysis was done by mutated TNF-R1 expression in TNF-R1 knock-out cells. Apoptosis (nuclear DNA fragmentation, caspase 3 assays), NF-κB activation and TNF-R1 internalization were used as biological readouts.
We identify dynamic S-palmitoylation as a new mechanism that controls selective TNF signaling. TNF-R1 itself is constitutively palmitoylated and depalmitoylated upon ligand binding. We identified the palmitoyl thioesterase APT2 to be involved in TNF-R1 depalmitoylation and TNF induced NF-κB activation. Mutation of the putative palmitoylation site C248 interferes with TNF-R1 localization to the plasma membrane and thus, proper signal transduction.
Our results introduce palmitoylation as a new layer of dynamic regulation of TNF-R1 induced signal transduction at a very early step of the TNF induced signaling cascade. Understanding the underlying mechanism may allow novel therapeutic options for disease treatment in future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. ...Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized ...SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.
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•Low avidity and broad cross-reactivities of pre-existing SARS-CoV-2 memory T cells•Strong CCCoV-specific memory CD4+ T cell responses in all analyzed individuals•SARS-CoV-2-specific CD4+ T cells in COVID-19 patients lack cross-reactivity to CCCoVs•Low avidity and clonality of SARS-CoV-2-specific T cell responses in severe COVID-19
Bacher et al. identify excessive but low-avidity T cell responses to SARS-CoV-2 as a hallmark of severe but not mild COVID-19. Pre-existing memory to SARS-CoV-2 in unexposed donors also displayed low avidity and harbored multiple, highly variable cross-reactivities that were not restricted to common cold coronaviruses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Proteolytic control of regulated necrosis Fuchslocher Chico, Johaiber; Saggau, Carina; Adam, Dieter
Biochimica et biophysica acta. Molecular cell research,
November 2017, 2017-Nov, 2017-11-00, 20171101, Volume:
1864, Issue:
11
Journal Article
Peer reviewed
Open access
Proteases control most of the physiological processes that occur in a cell. This particularly applies to apoptosis, the most well-studied form of cell death, where proteolysis by cysteine-aspartic ...proteases (caspases) is the primary mechanism for both initiation and execution of cell suicide. In contrast, the impact of proteolysis on other, non-apoptotic cell death pathways (summarized under the term “regulated necrosis”, RN) has long been enigmatic, but has clearly been confirmed by a number of recent groundbreaking discoveries. Here, we review these discoveries and provide an overview on the role of proteolysis in known forms of RN, with a particular focus on necroptosis and pyroptosis, and their regulation by deubiquitinases, apoptotic and inflammatory caspases. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
•Proteases control most of the physiological processes that occur in a cell.•Caspases are essential proteases for initiation and execution of apoptosis.•Proteolysis also controls non-apoptotic cell death (regulated necrosis).•Here, we review the role of proteolytic events in known forms of regulated necrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Ars moriendi: Proteases as sculptors of cellular suicide Heib, Michelle; Weiß, Jonas; Saggau, Carina ...
Biochimica et biophysica acta. Molecular cell research,
April 2022, 2022-04-00, 20220401, Volume:
1869, Issue:
4
Journal Article
Peer reviewed
Open access
The Ars moriendi, which translates to “The Art of Dying,” encompasses two Latin texts that gave advice on how to die well and without fear according to the Christian precepts of the late Middle Ages. ...Given that ten to hundred billion cells die in our bodies every day, it is obvious that the concept of a well and orderly (“regulated”) death is also paramount at the cellular level. In apoptosis, as the most well-studied form of regulated cell death, proteases of the caspase family are the central mediators. However, caspases are not the only proteases that act as sculptors of cellular suicide, and therefore, we here provide an overview of the impact of proteases in apoptosis and other forms of regulated cell death.
•Every day, billions of cells die in our body, and this must happen in a well and orderly, i.e., regulated manner.•Proteases of the caspase family are the central mediators in apoptosis as the best studied form of regulated cell death.•Other forms of regulated cell death depend on the action of caspases as well as non-caspase proteases.•Here, were provide an overview of the role of proteases as sculptors of cellular suicide.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this ...heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4+ T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4+ T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly.
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•SARS-CoV-2-specific T cell expansion rate indicates immune-response quality•Naive and memory pre-exposure repertoires inversely predict vaccine-response quality•Pre-existing memory T cells are excluded from high-quality vaccination responses•Impaired antigen-specific pre-exposure T cell repertoire as a hallmark of immune aging
Determinants of immune-response quality to SARS-CoV-2 remain poorly defined. Saggau et al. examine spike-specific naive and memory T cells pre- and post-vaccination and track pre-existing memory T cell receptors. They define T cell parameters of high-quality vaccine responses and identify high pre-existing memory and low naive T cell contributions as predictors of low-quality responses, particularly in the elderly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells ...are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.
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•Alcohol increases intestinal C. albicans-specific Th17 cells that migrate to the liver•An antifungal agent reduces C. albicans-specific Th17 cells in the liver•Adoptive transfer of C. albicans-specific Th17 cells promotes liver disease•C. albicans-specific Th17 cells promote liver disease via IL17ra on Kupffer cells
How fungal dysbiosis contributes to alcohol-associated liver disease is unclear. Zeng et al. find that C. albicans-specific Th17 cells increase in the blood and liver of patients with alcohol-associated liver disease. In mice, C. albicans-specific Th17 cells migrate from the intestine to the liver, where they contribute to ethanol-induced liver disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis ...factor‐α (TNF‐α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre‐VOC strain and the BA.2 virus were investigated in these at‐risk patients. Serum levels of anti‐SARS‐CoV‐2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti‐TNF‐α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease‐modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS‐CoV‐2‐specific B‐ and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti‐SARS‐CoV‐2 IgG levels, IgG avidity and anti‐pre‐VOC NA titres were significantly reduced in anti‐TNF‐α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti‐TNF‐α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS‐CoV‐2‐specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti‐BA.2 NA titres compared to both other groups. We show a reduced SARS‐CoV‐2 neutralizing capacity in patients under TNF‐α blockade. In this cohort, the plasma cell response appears to be less specific and shows stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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