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. 2021 Mar 15:173:379-398.
doi: 10.1016/j.ijbiomac.2021.01.120. Epub 2021 Jan 20.

New insights into Vitamin C function: Vitamin C induces JAK2 activation through its receptor-like transporter SVCT2

Zhuo Han  1 , Zihan Zhang  1 , Yian Guan  1 , Bingxue Chen  1 , Mengying Yu  1 , Lei Zhang  1 , Jingshuai Fang  1 , Yuan Gao  2 , Zekun Guo  3
Affiliations

New insights into Vitamin C function: Vitamin C induces JAK2 activation through its receptor-like transporter SVCT2

Zhuo Han et al. Int J Biol Macromol. .

Abstract

Vitamin C (VitC) is a requisite nutrient for humans and other primates. Extensive research continuously illustrates the applications of VitC in promoting cell reprogramming, fine-tuning embryonic stem cell function, and fighting diseases. Given its chemical reduction property, VitC predominantly acts as an antioxidant to reduce reactive oxygen species (ROS) and as a cofactor for certain dioxygenases involved in epigenetic regulation. Here, we propose that VitC is also a bio-signaling molecule based on the finding that sodium-dependent VitC transporter (SVCT) 2 is a novel receptor-like transporter of VitC that possesses dual activities in mediating VitC uptake and Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 2 signaling pathway. Through interaction, SVCT2 induces JAK2 phosphorylation while transporting VitC into cells. Activated JAK2 phosphorylates the C-terminus of SVCT2, resulting in the recruitment and activation of STAT2. As a highlight, our results suggest that the activation of JAK2 synergistically promotes regulation of VitC in ROS scavenging and epigenetic modifications through phosphorylating pyruvate dehydrogenase kinase 1, ten-eleven translocation enzyme 3, and histone H3 Tyr41. Furthermore, VitC-activated JAK2 exhibits bidirectional effects in regulating cell pluripotency and differentiation. Our results thus reveal that the SVCT2-mediated JAK2 activation facilitates VitC functions in a previously unknown manner.

Keywords: JAK2; SVCT2; TET3; Tyrosine phosphorylation; Vitamin C.

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Conflict of interest statement

Declaration of competing interest The authors declare no competing interest.

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