The role of lysosomes as intermediates in betacoronavirus PHEV egress from nerve cells

Author:

Wang Zhenzhen1,He Wenqi1ORCID,Li Caili1,Chen Yuzhu1,Li Zi1,Jiao Yubo1,Zhang Jing1,Shi Junchao1,Wang Gaili2,Guan Jiyu1,Zhao Kui1,Song Deguang1,Gao Feng1,Lan Yungang1ORCID

Affiliation:

1. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, Jilin, China

2. Jilin Academy of Animal Husbandry and Veterinary Medicine, Changchun, Jilin, China

Abstract

ABSTRACT The traditional view that betacoronaviruses exit occurs via the constitutive secretory route has recently been questioned by studies suggesting that this process involves lysosomal exocytosis. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, traffics to lysosomes prior to engaging in Arl8b-dependent lysosomal exocytosis. Notably, PHEV induces active or passive lysosomal acidification and activates lysosomal degradative enzymes. PHEV release depends on vacuolar H + -ATPase-mediated lysosomal acidification. In addition, PHEV transmission and PHEV-induced brain damage in the central nervous system can be blocked by the Rab7 GTPase competitive inhibitor CID1067700. Taken together, lysosome plays a critical role in PHEV egress in vitro and in vivo . IMPORTANCE Betacoronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mouse hepatitis virus (MHV), exploit the lysosomal exocytosis pathway for egress. However, whether all betacoronaviruses members use the same pathway to exit cells remains unknown. Here, we demonstrated that porcine hemagglutinating encephalomyelitis virus (PHEV) egress occurs by Arl8b-dependent lysosomal exocytosis, a cellular egress mechanism shared by SARS-CoV-2 and MHV. Notably, PHEV acidifies lysosomes and activates lysosomal degradative enzymes, while SARS-CoV-2 and MHV deacidify lysosomes and limit the activation of lysosomal degradative enzymes. In addition, PHEV release depends on V-ATPase-mediated lysosomal pH. Furthermore, this is the first study to evaluate βCoV using lysosome for spreading through the body, and we have found that lysosome played a critical role in PHEV neural transmission and brain damage caused by virus infection in the central nervous system. Taken together, different betacoronaviruses could disrupt lysosomal function differently to exit cells.

Funder

MOST | National Natural Science Foundation of China

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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