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WLS/无义突变型 Wnt 蛋白是必需的，它通过一种非 WNT 信号通路的机制来控制树突状细胞的体内平衡。

WLS/wntless is essential in controlling dendritic cell homeostasis via a WNT signaling-independent mechanism.

机构信息

Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.

D Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

出版信息

Autophagy. 2021 Dec;17(12):4202-4217. doi: 10.1080/15548627.2021.1907516. Epub 2021 Apr 14.

DOI:10.1080/15548627.2021.1907516
PMID:
33853474
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8726611/
Abstract

We propose that beyond its role in WNT secretion, WLS/GPR177 (wntless, WNT ligand secretion mediator) acts as an essential regulator controlling protein glycosylation, endoplasmic reticulum (ER) homeostasis, and dendritic cell (DC)-mediated immunity. WLS deficiency in bone marrow-derived DCs (BMDCs) resulted in poor growth and an inability to mount cytokine and T-cell responses , phenotypes that were irreversible by the addition of exogenous WNTs. In fact, WLS was discovered to integrate a protein complex in N-glycan-dependent and WLS domain-selective manners, comprising ER stress sensors and lectin chaperones. WLS deficiency in BMDCs led to increased ER stress response and macroautophagy/autophagy, decreased calcium efflux from the ER, and the loss of CALR (calreticulin)-CANX (calnexin) cycle, and hence protein hypo-glycosylation. Consequently, DC-specific -null mice were unable to develop both Th1-, Th2- and Th17-associated responses in the respective autoimmune and allergic disease models. These results suggest that WLS is a critical chaperone in maintaining ER homeostasis, glycoprotein quality control and calcium dynamics in DCs.: ATF6: activating transcription factor 6; ATG5: autophagy related 5; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATP2A1/SERCA1: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; BALF: bronchoalveolar lavage fluid; BFA: brefeldin A; BMDC: bone marrow-derived dendritic cell; CALR: calreticulin; CANX: calnexin; CCL2/MCP-1: C-C motif chemokine ligand 2; CNS: central nervous system; CT: C-terminal domain; DTT: dithiothreitol; DNAJB9/ERDJ4: DnaJ heat shock protein family (Hsp40) member B9; EAE: experimental autoimmune encephalomyelitis; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1/IRE1: endoplasmic reticulum (ER) to nucleus signaling 1; GFP: green fluorescent protein; HSPA5/GRP78/BiP: heat shock protein A5; IFNA: interferon alpha; IFNAR1: interferon alpha and beta receptor subunit 1; IFNB: interferon beta; IFNG/INFγ: interferon gamma; IFNGR2: interferon gamma receptor 2; IL6: interleukin 6; IL10: interleukin 10; IL12A: interleukin 12A; IL23A: interleukin 23 subunit alpha; ITGAX/CD11c: integrin subunit alpha X; ITPR1/InsP3R1: inositol 1,4,5-trisphosphate receptor type 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; OVA: ovalbumin; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLF: predicted lipocalin fold; PPP1R15A/GADD34: protein phosphatase 1 regulatory subunit 15A; RYR1/RyanR1: ryanodine receptor 1, skeletal muscle; SD: signal domain; TGFB/TGF-β: transforming growth factor beta family; Th1: T helper cell type 1; Th17: T helper cell type 17; TM: tunicamycin; TNF/TNF-α: tumor necrosis factor; UPR: unfolded protein response; WLS/wntless: WNT ligand secretion mediator.

摘要

我们提出，除了在 WNT 分泌中的作用外，WLS/GPR177（无 WNT 分泌、WNT 配体分泌调节剂）还作为一种重要的调节剂，控制蛋白质糖基化、内质网（ER）稳态和树突状细胞（DC）介导的免疫。骨髓来源的 DC（BMDC）中的 WLS 缺陷导致生长不良和无法产生细胞因子和 T 细胞反应的表型，这些表型通过添加外源性 WNTs 无法逆转。事实上，WLS 被发现以依赖 N-聚糖和 WLS 结构域选择性的方式整合一个蛋白质复合物，包括 ER 应激传感器和凝集素伴侣。BMDC 中的 WLS 缺陷导致 ER 应激反应和自噬/自噬增加，内质网钙流出减少，以及 CALR（钙网蛋白）-CANX（钙联蛋白）循环丧失，从而导致蛋白质低聚糖化。因此，DC 特异性 -null 小鼠无法在各自的自身免疫和过敏疾病模型中发展 Th1、Th2 和 Th17 相关反应。这些结果表明，WLS 是维持 ER 稳态、糖蛋白质量控制和钙动力学的关键伴侣在 DC 中。: ATF6: 激活转录因子 6; ATG5: 自噬相关 5; ATG12: 自噬相关 12; ATG16L1: 自噬相关 16 样 1; ATP2A1/SERCA1: 肌浆/内质网 Ca2+转运 1 的 ATP 酶; BALF: 支气管肺泡灌洗液; BFA: 布雷菲德菌素 A; BMDC: 骨髓来源的树突状细胞; CALR: 钙网蛋白; CANX: 钙联蛋白; CCL2/MCP-1: C-C 基序趋化因子配体 2; CNS: 中枢神经系统; CT: C 端结构域; DTT: 二硫苏糖醇; DNAJB9/ERDJ4: DnaJ 热休克蛋白家族（Hsp40）成员 B9; EAE: 实验性自身免疫性脑脊髓炎; EIF2A/eIF2α: 真核翻译起始因子 2A; EIF2AK3/PERK: 真核翻译起始因子 2α激酶 3; ERN1/IRE1: 内质网（ER）向核信号 1; GFP: 绿色荧光蛋白; HSPA5/GRP78/BiP: 热休克蛋白 A5; IFNA: 干扰素 alpha; IFNAR1: 干扰素 alpha 和 beta 受体亚单位 1; IFNB: 干扰素 beta; IFNG/INFγ: 干扰素 gamma; IFNGR2: 干扰素 gamma 受体 2; IL6: 白细胞介素 6; IL10: 白细胞介素 10; IL12A: 白细胞介素 12A; IL23A: 白细胞介素 23 亚单位 alpha; ITGAX/CD11c: 整合素亚单位 alpha X; ITPR1/InsP3R1: 肌醇 1,4,5-三磷酸受体 1 型; MAP1LC3B/LC3B: 微管相关蛋白 1 轻链 3 beta; OVA: 卵清蛋白; PIK3C3/VPS34: 磷脂酰肌醇 3-激酶催化亚单位 3; PLF: 预测的脂联素折叠; PPP1R15A/GADD34: 蛋白磷酸酶 1 调节亚单位 15A; RYR1/RyanR1: 肌浆网钙释放通道 1，骨骼肌; SD: 信号域; TGFB/TGF-β: 转化生长因子 beta 家族; Th1: T 辅助细胞类型 1; Th17: T 辅助细胞类型 17; TM: 衣霉素; TNF/TNF-α: 肿瘤坏死因子; UPR: 未折叠蛋白反应; WLS/wntless: WNT 配体分泌调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/899f/8726611/4165e814a47e/KAUP_A_1907516_F0007_C.jpg
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