2. Academic Validation
  3. Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

  • Sci Adv. 2023 May 24;9(21):eadg1778. doi: 10.1126/sciadv.adg1778.
Zheng-Zhou Lu 1,  Cong Sun 1,  Xiaolin Zhang 1,  Yingying Peng 2,  Yan Wang 2,  Yan Zeng 3 4,  Nannan Zhu 1,  Yan Yuan 1 5,  Mu-Sheng Zeng 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center and Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Precision clinical laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong 524037, China.
  • 4 Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi 832000, China.
  • 5 Institute for Advanced Medical Research, Shandong University, Jinan, Shandong, China.
PMID: 37224259 DOI: 10.1126/sciadv.adg1778
Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) has been implicated in the pathogenesis of Kaposi's sarcoma (KS) and other malignancies. The cellular origin of KS has been suggested to be either mesenchymal stem cells (MSCs) or endothelial cells. However, receptor(s) for KSHV to infect MSCs remains unknown. By combining bioinformatics analysis and shRNA screening, we identify neuropilin 1 (NRP1) as an entry receptor for KSHV Infection of MSCs. Functionally, NRP1 knockout and overexpression in MSCs significantly reduce and promote, respectively, KSHV Infection. Mechanistically, NRP1 facilitated the binding and internalization of KSHV by interacting with KSHV glycoprotein B (gB), which was blocked by soluble NRP1 protein. Furthermore, NRP1 interacts with TGF-β Receptor type 2 (TGFBR2) through their respective cytoplasmic domains and thus activates the TGFBR1/2 complex, which facilitates the macropinocytosis-mediated KSHV internalization via the small GTPases Cdc42 and Rac1. Together, these findings implicate that KSHV has evolved a strategy to invade MSCs by harnessing NRP1 and TGF-beta receptors to stimulate macropinocytosis.

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