ARTC1-mediated VAPB ADP-ribosylation regulates calcium homeostasis
ARTC1-mediated VAPB ADP-ribosylation regulates calcium homeostasis
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DOI：
10.1093/jmcb/mjad043
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发表时间：
2024-01-05
影响因子：
5.5
通讯作者：
Wu，Chen
中科院分区：
文献类型：
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作者：
Ma，Xueyao;Li，Mengyuan;Wu，Chen
单ADP核糖基化（MARylation）是一种翻译后修饰，可调节多种生物学过程，包括DNA损伤修复、细胞增殖、代谢以及应激和免疫反应。在哺乳动物中，MAR化主要由ADP-核糖基转移酶（ART）催化，其由两组组成：ART霍乱毒素样（ARTC）和ART白喉毒素样（ARTD，也称为PARP）。人类ARTC（hARTC）家族由四个成员组成：两种活性单ADP-ART（hARTC 1和hARTC 5）和两种无酶活性的酶（hARTC 3和hARTC 4）。在这项研究中，我们系统地研究了hARTC家族的同源性，表达和定位模式，特别关注hARTC 1。我们的研究结果表明，hARTC 3与hARTC 1相互作用，并通过稳定hARTC 1来促进hARTC 1的酶活性。我们还鉴定了囊泡相关膜蛋白相关蛋白B（VAP B）作为hARTC 1的新靶点，并确定VAP B的Arg 50为ADP核糖基化位点。此外，我们证明hARTC 1的敲除会损害细胞内钙稳态，强调了hARTC 1介导的VAPB Arg 50 ADP核糖基化在调节钙稳态中的功能重要性。总之，我们的研究确定了hARTC 1在内质网中的新靶点，并表明ARTC 1在调节钙信号传导中起作用。
Mono-ADP-ribosylation (MARylation) is a post-translational modification that regulates a variety of biological processes, including DNA damage repair, cell proliferation, metabolism, and stress and immune responses. In mammals, MARylation is mainly catalyzed by ADP-ribosyltransferases (ARTs), which consist of two groups: ART cholera toxin-like (ARTCs) and ART diphtheria toxin-like (ARTDs, also known as PARPs). The human ARTC (hARTC) family is composed of four members: two active mono-ADP-ARTs (hARTC1 and hARTC5) and two enzymatically inactive enzymes (hARTC3 and hARTC4). In this study, we systematically examined the homology, expression, and localization pattern of the hARTC family, with a particular focus on hARTC1. Our results showed that hARTC3 interacted with hARTC1 and promoted the enzymatic activity of hARTC1 by stabilizing hARTC1. We also identified vesicle-associated membrane protein-associated protein B (VAPB) as a new target of hARTC1 and pinpointed Arg50 of VAPB as the ADP-ribosylation site. Furthermore, we demonstrated that knockdown ofhARTC1impaired intracellular calcium homeostasis, highlighting the functional importance of hARTC1-mediated VAPB Arg50 ADP-ribosylation in regulating calcium homeostasis. In summary, our study identified a new target of hARTC1 in the endoplasmic reticulum and suggested that ARTC1 plays a role in regulating calcium signaling.