Death receptor 6 contributes to autoimmunity in lupus-prone mice

Fujikura, Daisuke; Ikesue, Masahiro; Endo, Toshihiko; Chiba, Shuya; Higashi, Hideaki; Uede, Toshimitsu

doi:10.1038/ncomms13957

Cited by 21 publications

(15 citation statements)

References 54 publications

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“…This is reminiscent of death receptor 6, a member of the TNF receptor superfamily. Full-length DR6 can act as a surface receptor transmitting cell death signals (Nikolaev et al, 2009;Mi et al, 2011;Strilic et al, 2016;Fujikura et al, 2017;Gamage et al, 2017), while the ADAM10-cleaved DR6 ectodomain can act as a cytokine suppressing proliferation of Schwann cells and delaying myelination in the peripheral nervous system (Colombo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

et al. 2019

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The metalloprotease ADAM 10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein ( APP ) and lowers amyloid‐beta. Yet, ADAM 10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM 10 activation. However, they may also serve—in addition to APP —as biomarkers to monitor ADAM 10 activity in patients and to develop APP ‐selective ADAM 10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein Nr CAM . ADAM 10 controlled Nr CAM surface levels and regulated neurite outgrowth in vitro in an Nr CAM ‐dependent manner. However, ADAM 10 cleavage of Nr CAM , in contrast to APP , was not stimulated by the ADAM 10 activator acitretin, suggesting that substrate‐selective ADAM 10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM 10, spared most other ADAM 10 substrates in brain, including Nr CAM . Taken together, this study demonstrates an Nr CAM ‐dependent function for ADAM 10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM 10 activation is possible and may be monitored with Nr CAM .

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Section: Discussionmentioning

confidence: 99%

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

et al. 2019

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“…Tagging syndecan constructs at the C-terminus interferes with their correct processing and targeting (Maday et al, 2008), and tagging at the N-terminus may also interfere with syndecan functions since the major ligand-binding HS chains are attached near the N-terminus in all four syndecans. However, syndecan-1 His-tagged at the N-terminus has been shown to retain its ability to bind to death receptor 6 (Fujikura et al, 2017), suggesting that N-terminal tagging may not interfere with activity, although the activity and HS structure of tagged syndecan-1 were not rigorously compared to those of the native counterpart.…”

Section: Isolation Of Syndecansmentioning

confidence: 99%

Isolation and functional analysis of syndecans

Park

2018

Methods in Extracellular Matrix Biology

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Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs). Syndecans are composed of sulfated glycosaminoglycans (GAGs), heparan sulfate (HS) or both HS and chondroitin sulfate (CS), attached covalently to core proteins. Syndecans regulate many cellular processes, such as adhesion, proliferation, and migration. Syndecans bind and regulate molecules primarily through their HS chains, but do not bind to all HS/heparin-binding molecules. Furthermore, mice ablated for the syndecan-1 or -4 gene do not show major developmental abnormalities, but they do show striking pathological phenotypes when challenged with infectious or inflammatory stimuli and conditions, suggesting that certain functions of syndecans are specific and cannot be compensated for by other syndecans or other HSPGs. These observations underscore the physiological importance of syndecans and indicate a need to study the activities of isolated native syndecans to define their molecular and cellular functions, and to establish their biological significance. Here we describe methods to isolate syndecans and several assays to analyze their functions.

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“…DR6 is also expressed in oligodendrocytes, which are the myelinating cells in the CNS. Additionally, DR6 controls proliferation and differentiation of immune cells (Zhao et al, 2001;Schmidt et al, 2003;DeRosa et al, 2008), and was recently shown to contribute to tumor cell-induced endothelial cell necroptosis and autoimmunity in lupus-prone mice (Strilic et al, 2016;Fujikura et al, 2017). Consequently, DR6 has been linked to Alzheimer's disease and is considered as a drug target for multiple sclerosis (Nikolaev et al, 2009;Mi et al, 2011;Kallop et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, DR6 has been linked to Alzheimer's disease and is considered as a drug target for multiple sclerosis (Nikolaev et al, 2009;Mi et al, 2011;Kallop et al, 2014). Additionally, DR6 controls proliferation and differentiation of immune cells (Zhao et al, 2001;Schmidt et al, 2003;DeRosa et al, 2008), and was recently shown to contribute to tumor cell-induced endothelial cell necroptosis and autoimmunity in lupus-prone mice (Strilic et al, 2016;Fujikura et al, 2017). In these processes, DR6 acts cell-autonomously as a membrane-bound receptor, similar to the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

et al. 2018

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Death receptor 6 (DR6) is an orphan member of the TNF receptor superfamily and controls cell death and differentiation in a cell-autonomous manner in different cell types. Here, we report an additional non-cell-autonomous function for DR6 in the peripheral nervous system (PNS). DR6-knockout (DR6 KO) mice showed precocious myelination in the PNS Using an myelination assay, we demonstrate that neuronal DR6 acts in on Schwann cells (SCs) and reduces SC proliferation and myelination independently of its cytoplasmic death domain. Mechanistically, DR6 was found to be cleaved in neurons by "a disintegrin and metalloprotease 10" (ADAM10), releasing the soluble DR6 ectodomain (sDR6). Notably, in the myelination assay, sDR6 was sufficient to rescue the DR6 KO phenotype. Thus, in addition to the cell-autonomous receptor function of full-length DR6, the proteolytically released sDR6 can unexpectedly also act as a paracrine signaling factor in the PNS in a non-cell-autonomous manner during SC proliferation and myelination. This new mode of DR6 signaling will be relevant in future attempts to target DR6 in disease settings.

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Death receptor 6 contributes to autoimmunity in lupus-prone mice

Cited by 21 publications

References 54 publications

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Isolation and functional analysis of syndecans

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

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