Pleiotropy of the Drosophila JAK pathway cytokine Unpaired 3 in development and aging

Wang, Liqun; Sexton, Travis; Venard, C.; Giedt, Michelle S.; Guo, Qin; Chen, Qian; Harrison, Douglas A.

doi:10.1016/j.ydbio.2014.09.015

Cited by 35 publications

(25 citation statements)

References 96 publications

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“…os s affects expression of the cytokines upd1 and upd3 , and impairs induction of upd3 by infection with non-pathogenic bacteria1424. We observed that os s mutants did not activate upd3 expression to the same degree as wild-type flies after M marinum infection, whereas upd1 expression was not induced by M. marinum infection in wild-type flies or os s mutants (Fig.…”

Section: Resultsmentioning

confidence: 69%

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

et al. 2017

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Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum, mycobacterium-induced STAT activity triggered by unpaired-family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila.

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Section: Resultsmentioning

confidence: 69%

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

et al. 2017

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“…For misexpression of transgenes, we utilized the GAL4/UAS system in flies [36]. The following stocks were gifts from Douglas A. Harrison: UAS-ET (FBal0264424) [40]; y 1 , sc*, v 1 ; UAS-dome RNAi (RRID:BDSC_32860) [37]; y 1 , v 1 ; UAS-Stat92E RNAi (RRID:BDSC_33637) [37]; w*; UAS-hop/ CyO (RRID:BDSC_79033) [41]; Upd-GAL4, w* (RRID: BDSC_26796); UAS-iupd3 (FBal0177288) [42]; Upd3-GAL4, UAS-upd3-GFP/CyO; Dr/TM6B (cross between FBal0181583 and FBal0302834) [27]; and y 1 , sc*, v 1 ; UAS-upd3 RNAi (RRID:BDSC_32859) [43]. The following stocks were gifts from Douglas A. Harrison: UAS-ET (FBal0264424) [40]; y 1 , sc*, v 1 ; UAS-dome RNAi (RRID:BDSC_32860) [37]; y 1 , v 1 ; UAS-Stat92E RNAi (RRID:BDSC_33637) [37]; w*; UAS-hop/ CyO (RRID:BDSC_79033) [41]; Upd-GAL4, w* (RRID: BDSC_26796); UAS-iupd3 (FBal0177288) [42]; Upd3-GAL4, UAS-upd3-GFP/CyO; Dr/TM6B (cross between FBal0181583 and FBal0302834) [27]; and y 1 , sc*, v 1 ; UAS-upd3 RNAi (RRID:BDSC_32859) [43].…”

Section: Fly Stocks and Culturementioning

confidence: 99%

“…The following stocks were obtained from the Bloomington Drosophila Stock Center, Bloomington, In, USA (supported by NIH grant P40OD018537) and used in this study: w*; Btl-GAL4, UAS-Act5C:GFP/CyO, lacZ (RRID:BDSC_8807); w 1118 , UAS-Dcr-2; Pin 1 /CyO (RRID: BDSC_24644); w 1118 ; 10XStat92E-GFP (RRID:BDSC_26197); UAS-os RNAi (RRID:BDSC_28722) [37]; UAS-upd RNAi (RRID:BDSC_33680) [38]; UAS-os2 RNAi (RRID: BDSC_33949) [37]; UAS-upd2 RNAi (RRID:BDSC_33988) [38]; w*, upd2D (RRID:BDSC_55727) [22]; and hs-FLP; Act5-C>y + >GAL4, UAS-GFP [39]. The following stocks were gifts from Douglas A. Harrison: UAS-ET (FBal0264424) [40]; y 1 , sc*, v 1 ; UAS-dome RNAi (RRID:BDSC_32860) [37]; y 1 , v 1 ; UAS-Stat92E RNAi (RRID:BDSC_33637) [37]; w*; UAS-hop/ CyO (RRID:BDSC_79033) [41]; Upd-GAL4, w* (RRID: BDSC_26796); UAS-iupd3 (FBal0177288) [42]; Upd3-GAL4, UAS-upd3-GFP/CyO; Dr/TM6B (cross between FBal0181583 and FBal0302834) [27]; and y 1 , sc*, v 1 ; UAS-upd3 RNAi (RRID:BDSC_32859) [43].…”

Section: Fly Stocks and Culturementioning

confidence: 99%

“…Humans and mice possess four JAKs (JAK1-3 and Tyk2) [13] and seven STATs (STAT1-4, 5A, 5B, and 6) [14], together mediating processes including hematopoiesis [15], stem cell maintenance [16], lung development [17,18], and immune response [19]. This pathway's activity is likewise required for the same phenomena in Drosophila [20][21][22][23][24][25][26], among others [27][28][29][30][31][32], though the pathway involves only one transmembrane receptor [Domeless (Dome)], one JAK [Hopscotch (Hop)], one STAT (Stat92E), and three activating ligands (Upd1-3). The role of JAK/STAT signaling in these events is governed by its more general involvement with cell migration, differentiation, and proliferation.…”

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confidence: 99%

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JAK/STAT signaling is involved in air sac primordium development of Drosophila melanogaster

Powers

Srivastava

2019

FEBS Letters

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The dorsal thoracic air sacs in fruit flies (Drosophila melanogaster) are functionally and developmentally comparable to human lungs. The progenitors of these structures, air sac primordia (ASPs), invasively propagate into wing imaginal disks, employing mechanisms similar to those that promote metastasis in malignant tumors. We investigated whether Janus kinase/signal transducer and activator of transcription JAK/STAT signaling plays a role in the directed morphogenesis of ASPs. We find that JAK/STAT signaling occurs in ASP tip cells and misexpression of core components in the JAK/STAT signaling cascade significantly impedes ASP development. We further identify Upd2 as an activating ligand for JAK/STAT activity in the ASP. Together, these data constitute a considerable step forward in understanding the role of JAK/STAT signaling in ASPs and similar structures in mammalian models.

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“…For example, IL-6-deficient mice show reduce expansion of CD4 + T cells and autoimmune response 52 . In Drosophila , IL-6-like cytokine Upd3 plays a key role in intestinal stem cell homeostasis 53–55 , reproductive aging 56 , glucose homeostasis and lifespan 29 . Although unpaired family members, especially Upd2, have been shown to relays nutrient signals from fat body to brain 57 , the role of Upd3 in inter-tissue communication and systemic aging regulation has not been fully established.…”

Section: Discussionmentioning

confidence: 99%

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Huang

Miao

Chang

et al. 2019

Preprint

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27Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous 28 regulation of age-related cardiac dysfunction is poorly understood. In the present study, we 29 discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes 30(hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-31 autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is 32 significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is 33 sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent 34 induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in 35 aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal 36 import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates 37 aging-and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role 38 of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific 39 peroxisomal import in mediating non-autonomous regulation of cardiac aging. 41Age is a major risk factor for a wide range of human diseases 1 . For example, aging is 54 associated with a great increase in the incidence of cardiovascular diseases (CVD), one of the 55 leading causes of death worldwide 2, 3 . During aging, cardiomyocytes undergo rapid remodeling 56 with a variety of intracellular changes, in particular impaired mitochondrial quality control, 57 increased production of reactive oxygen species (ROS), and elevated inflammation 1 . The chronic 58 and systemic inflammation (or "inflammaging") is often associated with increased levels of 59 circulating pro-inflammatory biomarkers (e.g., interleukin-6/IL-6 and C-reactive protein/CRP), 60 which are notable risk factors for cardiovascular diseases 4, 5 . The cause of inflammaging and its 61 impact on cardiac aging are still poorly understood. It is known that short-term expression of 62 inflammatory cytokines (e.g., IL-6) can protect myocytes from injury-induced apoptosis. However, 63prolonged production of IL-6 induces pathological hypertrophy and decreases cardiomyocyte 64 contractility through the activation of Janus Kinases-Signal Transducer and Activator of 65 Transcription (JAK-STAT) signaling 6 . Elevated levels of circulating IL-6 are often associated with 66 heart failure, myocardial damage and atherosclerosis 6-8 . IL-6 can be produced not only by 67 cardiomyocytes themselves in response to ischemia-reperfusion injury and myocardial infarction, 68 but also by other neighboring tissues (e.g., endothelial cells and vascular smooth-muscle), 69 immune cells (e.g., monocytes and macrophages), as well as liver 7, 9 . However, the root causes 70 of inflammaging and the primary sources of these inflammatory factors remain to be determined. 71Liver is a major endocrine organ that produces a wide variety of systemic factors to 72 coordinate ...

show abstract

Pleiotropy of the Drosophila JAK pathway cytokine Unpaired 3 in development and aging

Cited by 35 publications

References 96 publications

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

JAK/STAT signaling is involved in air sac primordium development of Drosophila melanogaster

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

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