Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins

Kei Miyakawa, Mayuko Nishi, Michinaga Ogawa, Satoko Matsunaga, Masaya Sugiyama, Hironori Nishitsuji, Hirokazu Kimura, Makoto Ohnishi, Koichi Watashi, Kunitada Shimotohno, Takaji Wakita and Akihide Ryo ()
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Kei Miyakawa: Yokohama City University School of Medicine
Mayuko Nishi: Yokohama City University School of Medicine
Michinaga Ogawa: National Institute of Infectious Diseases
Satoko Matsunaga: Yokohama City University School of Medicine
Masaya Sugiyama: National Center for Global Health and Medicine
Hironori Nishitsuji: National Center for Global Health and Medicine
Hirokazu Kimura: Gunma Paz University
Makoto Ohnishi: National Institute of Infectious Diseases
Koichi Watashi: National Institute of Infectious Diseases
Kunitada Shimotohno: National Center for Global Health and Medicine
Takaji Wakita: National Institute of Infectious Diseases
Akihide Ryo: Yokohama City University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Autophagy has been linked to a wide range of functions, including a degradative process that defends host cells against pathogens. Although the involvement of autophagy in HBV infection has become apparent, it remains unknown whether selective autophagy plays a critical role in HBV restriction. Here, we report that a member of the galectin family, GAL9, directs the autophagic degradation of HBV HBc. BRET screening revealed that GAL9 interacts with HBc in living cells. Ectopic expression of GAL9 induces the formation of HBc-containing cytoplasmic puncta through interaction with another antiviral factor viperin, which co-localized with the autophagosome marker LC3. Mechanistically, GAL9 associates with HBc via viperin at the cytoplasmic puncta and enhanced the auto-ubiquitination of RNF13, resulting in p62 recruitment to form LC3-positive autophagosomes. Notably, both GAL9 and viperin are type I IFN-stimulated genes that act synergistically for the IFN-dependent proteolysis of HBc in HBV-infected hepatocytes. Collectively, these results reveal a previously undescribed antiviral mechanism against HBV in infected cells and a form of crosstalk between the innate immune system and selective autophagy in viral infection.

Date: 2022
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DOI: 10.1038/s41467-022-28171-5

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