SLC13A3

Last update 08 May 2025

Basic Info

Synonyms

hNaDC3, Na(+)/dicarboxylate cotransporter 3, NaDC-3

+ [7]

Introduction

High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate (PubMed:10794676, PubMed:10992006, PubMed:15561973, PubMed:17356845, PubMed:17426067, PubMed:24247155, PubMed:30635937). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:10794676, PubMed:10992006). Can transport citrate in a Na(+)-dependent manner, recognizing the divalent form of citrate rather than the trivalent form which is normally found in blood (PubMed:10794676).

100 Clinical Results associated with SLC13A3

100 Translational Medicine associated with SLC13A3

0 Patents (Medical) associated with SLC13A3

Literatures (Medical) associated with SLC13A3

01 Mar 2025·Nature Structural & Molecular Biology

Substrate translocation and inhibition in human dicarboxylate transporter NaDC3

Article

Author: Wang, Da-Neng ; Kuang, Huihui ; Becerril, Alissa ; Wang, Bing ; Li, Yan ; Marden, Jennifer J ; Song, Jinmei ; Mikusevic, Vedrana ; Rice, William J ; Mindell, Joseph A

The human high-affinity sodium-dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling molecules. Understanding the cellular signaling process and developing inhibitors require knowledge of the structural basis of the dicarboxylate specificity and inhibition mechanism of NaDC3. To this end, we determined the cryo-electron microscopy structures of NaDC3 in various dimers, revealing the protomer in three conformations: outward-open C_o, outward-occluded C_oo and inward-open C_i. A dicarboxylate is first bound and recognized in C_o and how the substrate interacts with NaDC3 in C_oo likely helps to further determine the substrate specificity. A phenylalanine from the scaffold domain interacts with the bound dicarboxylate in the C_oo state and modulates the kinetic barrier to the transport domain movement. Structural comparison of an inhibitor-bound structure of NaDC3 to that of the sodium-dependent citrate transporter suggests ways for making an inhibitor that is specific for NaDC3.

01 Feb 2025·Cell Metabolism

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1

Article

Author: Liu, Tianjie ; Fan, Yizeng ; Li, Mengxing ; Guo, Chendong ; Ding, Peng ; Jian, Yanlin ; Wei, Wenyi ; Wang, Zixi ; Wang, Yuzhao ; Liu, Bo ; Wei, Yi ; Lei, Yuzeshi ; Li, Lei ; Yan, Xiaolong ; Zeng, Jin ; Ma, Zhiqiang ; Dan, Weichao

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

01 Dec 2024·Cancer Cell

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance

Article

Author: Vatan, Linda ; Liao, Peng ; Sivaccumar, Jwala P. ; Zou, Weiping ; Tison, Kole ; Sivaccumar, Jwala P ; Vigil, Thomas ; Mortensen, Richard ; Pitter, Michael ; Du, Yuheng ; Kryczek, Ilona ; Yang, Hannah ; Wang, Weichao ; Garmire, Lana ; Wang, Shaomeng ; Zhang, Ningyan ; Yu, Jiali ; Lin, Heng ; An, Zhiqiang ; Shah, Yatrik M. ; Ramesh, Ashwin Kumar ; Kirchhoff, Paul ; Wei, Shuang ; Grove, Sara ; Kim, Chan ; Shah, Yatrik M ; Zhou, Jiajia

Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3⁺ cancer.

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SLC13A3

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