Xinxin Wang#，Zhiyuan Wen#，Huizhen Cao，Jie Luo，Lei Shuai，Chong Wang，Jinying Ge，Xijun Wang，Zhigao Bu，Jinliang Wang

J Virol.2023 Feb 13;e0161122.doi: 10.1128/jvi.01611-22. Online ahead of print.

Abstract

Identification of bona fide functional receptors and elucidation of the mechanism of receptor-mediated virus entry are important to reveal targets for developing therapeutics against rabies virus (RABV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our previous studies suggest that metabotropic glutamate receptor subtype 2 (mGluR2) functions as an entry receptor for RABV  in vitro , and is an important internalization factor for SARS-CoV-2  in vitro  and  in vivo . Here, we demonstrate that mGluR2 facilitates RABV internalization  in vitro  and infection  in vivo . We found that transferrin receptor 1 (TfR1) interacts with mGluR2 and internalizes with mGluR2 and RABV in the same clathrin-coated pit. Knockdown of TfR1 blocks agonist-triggered internalization of mGluR2. Importantly, TfR1 also interacts with the SARS-CoV-2 spike protein and is important for SARS-CoV-2 internalization. Our findings identify a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry, and reveal TfR1 as a potential target for therapeutics against RABV and SARS-CoV-2. IMPORTANCE We previously found that metabotropic glutamate receptor subtype 2 (mGluR2) is an entry receptor for RABV  in vitro , and an important internalization factor for SARS-CoV-2  in vitro  and  in vivo . However, whether mGluR2 is required for RABV infection  in vivo  was unknown. In addition, how mGluR2 mediates the internalization of RABV and SARS-CoV-2 needed to be resolved. Here, we found that mGluR2 gene knockout mice survived a lethal challenge with RABV. To our knowledge, mGluR2 is the first host factor to be definitively shown to play an important role in RABV street virus infection  in vivo . We further found that transferrin receptor protein 1 (TfR1) directly interacts and cooperates with mGluR2 to regulate the endocytosis of RABV and SARS-CoV-2. Our study identifies a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry and opens a new door for the development of therapeutics against RABV and SARS-CoV-2.

Keywords: SARS-CoV-2; TfR1; internalization; mGluR2; rabies virus.