Ubiquitin‐like protein <scp>MNSF</scp>β covalently binds to <scp>B</scp>cl–<scp>G</scp> and enhances lipopolysaccharide/interferon γ‐induced apoptosis in macrophages

Watanabe, Jun; Nakagawa, Mai; Watanabe, Natsuko; Nakamura, Morihiko

doi:10.1111/febs.12120

Cited by 22 publications

(15 citation statements)

References 34 publications

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“…In particular, the decidual immune cells−predominantly natural‐killer cells and macrophages−preserve a hospitable microenvironment for pregnancy to proceed (Jensen et al, ; Kajihara et al, ), which includes the controlled upregulation of an apoptotic response. Given that MNSFB also regulates apoptosis via its interaction with the proapoptotic proteins BCL‐G and P53 (Pickard et al, ; Siew et al, ; Watanabe et al, ), we suggest that a deficiency in MNSFB levels is responsible for the down‐regulated uterine expression of BCL‐G and P53 (Fig. ).…”

Section: Discussionmentioning

confidence: 68%

Deficiency of monoclonal non‐specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice

Zhang

et al. 2015

Molecular Reproduction Devel

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Maternal immune tolerance to the semi-allogenic fetus is required for successful pregnancy in mammals. Monoclonal nonspecific suppressor factor beta (MNSFB) is an immunosuppressive factor present in uterine epithelial and stromal cells, as well as in macrophages and T cells. Although the functional neutralization of MNSFB using specific antibodies against it lead to failed embryo implantation in mice, the exact role of MNSFB at the fetal-maternal interface remains unclear. The present study generated conditional heterozygous Mnsfb-deficient (Mnsfb(+/) (-) ) mice using the LoxP/Cre system. Western-blot analyses showed that uterine MNSFB protein in Mnsfb(+/-) mice was remarkably down-regulated compared to that in the wild-type (Mnsfb(+/+) ) mice. The litter size of female Mnsfb(+/-) mice was significantly reduced, which corresponded to developmental failure of embryos beyond Day 11 of pregnancy. The expression level of MNSFB protein was also lower in the failing compared to the normal embryos. An aberrant interaction between the embryos of Day-4 pregnant wild-type mice and endometrial stromal cells of female Mnsfb(+/-) mice was observed in vitro. The uterine Day-5 abundance of P53, BAX, and BCL-G in pregnant Mnsfb(+/-) mice was significantly decreased compared to that of wild-type mice, whereas the expression of P27 and tumor necrosis factor alpha (TNFA) was elevated. By comparison, the levels of MNSFB and BAX proteins in human decidual tissues obtained from recurrent spontaneous miscarriage patients were significantly reduced compared to those obtained from legal medial abortion, highlighting the involvement of MNSFB in the pathogenesis of recurrent spontaneous miscarriage. Together, these results demonstrated that a deficiency in MNSFb is associated with pregnancy loss, probably through reduced P53 and/or increased TNFA production at the fetal-maternal interface.

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Section: Discussionmentioning

confidence: 68%

Deficiency of monoclonal non‐specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice

Zhang

et al. 2015

Molecular Reproduction Devel

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“…The killing capacity of endogenous BCL-G was supported by subsequent studies in human osteosarcoma 9 , breast 11 and prostate 12 cancer cell lines, which showed a protective effect of BCL-G depletion during p53 activation or UV irradiation. Other reports, while suggesting a proapoptotic role of BCL-G, lacked a conclusive support for the observed cell death being directly controlled by BCL-G alone 34 . Here, we report that in human IEC and intestinal organoids expression of BCL-G S/L paralleled induction of apoptosis by IFN-γ and TNF-α, where it converged with activation of caspase-9, suggesting engagement of the mitochondrial pathway.…”

Section: Discussionmentioning

confidence: 91%

Human BCL-G regulates secretion of inflammatory chemokines but is dispensable for induction of apoptosis by IFN-γ and TNF-α in intestinal epithelial cells

et al. 2020

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Proteins of the BCL-2 family are evolutionarily conserved modulators of apoptosis that function as sensors of cellular integrity. Over the past three decades multiple BCL-2 family members have been identified, many of which are now fully incorporated into regulatory networks governing the mitochondrial apoptotic pathway. For some, however, an exact role in cell death signalling remains unclear. One such 'orphan' BCL-2 family member is BCL-G (or BCL2L14). In this study we analysed gastrointestinal expression of human BCL-G in health and disease states, and investigated its contribution to inflammation-induced tissue damage by exposing intestinal epithelial cells (IEC) to IFN-γ and TNF-α, two pro-inflammatory mediators associated with gut immunopathology. We found that both BCL-G splice variants -BCL-G S (short) and BCL-G L (long)were highly expressed in healthy gut tissue, and that their mRNA levels decreased in active inflammatory bowel diseases (for BCL-G S ) and colorectal cancer (for BCL-G S/L ). In vitro studies revealed that IFN-γ and TNF-α synergised to upregulate BCL-G S/L and to trigger apoptosis in colonic epithelial cell lines and primary human colonic organoids. Using RNAi, we showed that synergistic induction of IEC death was STAT1-dependent while optimal expression of BCL-G S/L required STAT1, NF-κB/p65 and SWI/SNF-associated chromatin remodellers BRM and BRG1. To test the direct contribution of BCL-G to the effects of IFN-γ and TNF-α on epithelial cells, we used RNAi-and CRISPR/Cas9-based perturbations in parallel with isoform-specific overexpression of BCL-G, and found that BCL-G was dispensable for Th1 cytokine-induced apoptosis of human IEC. Instead, we discovered that depletion of BCL-G differentially affected secretion of inflammatory chemokines CCL5 and CCL20, thus uncovering a non-apoptotic immunoregulatory function of this BCL-2 family member. Taken together, our data indicate that BCL-G may be involved in shaping immune responses in the human gut in health and disease states through regulation of chemokine secretion rather than intestinal apoptosis.

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“…In contrast, we found an increased association between GIT2 and Rpl17 (ribosomal protein L17), Fau/MNSFβ (Monoclonal non-specific suppressor factor β), and Fbxo24 (F-Box Only Protein 24/IKK1) in the pathological db/db state. Interestingly, both Fau/MNSFβ and Fbxo24 are associated with apoptotic activity linked to inflammation and DNA damage ( 108 , 109 ). Proteins commonly co-precipitating with GIT2 in both WT and db/db conditions (Map1a, Pdrg1, Caskin2) were also validated and were found to equally associate with GIT2 in both conditions (Figure 10 D).…”

Section: Resultsmentioning

confidence: 99%

GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging

et al. 2016

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Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional “keystone” role in regulating the aging process by coordinating somatic responses to energy deficits.

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Ubiquitin‐like protein MNSFβ covalently binds to Bcl–G and enhances lipopolysaccharide/interferon γ‐induced apoptosis in macrophages

Cited by 22 publications

References 34 publications

Deficiency of monoclonal non‐specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice

Deficiency of monoclonal non‐specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice

Human BCL-G regulates secretion of inflammatory chemokines but is dispensable for induction of apoptosis by IFN-γ and TNF-α in intestinal epithelial cells

GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging

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