The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro

Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that...

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Published in:	PLoS pathogens Vol. 18; no. 3; p. e1009983
Main Authors:	Gad, Sameh A, Sugiyama, Masaya, Tsuge, Masataka, Wakae, Kosho, Fukano, Kento, Oshima, Mizuki, Sureau, Camille, Watanabe, Noriyuki, Kato, Takanobu, Murayama, Asako, Li, Yingfang, Shoji, Ikuo, Shimotohno, Kunitada, Chayama, Kazuaki, Muramatsu, Masamichi, Wakita, Takaji, Nozaki, Tomoyoshi, Aly, Hussein H
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-03-2022 Public Library of Science (PLoS)
Subjects:	Adenosine triphosphatase Agonists Biology and life sciences Care and treatment Cell division Cell surface Depletion Development and progression Dynein Family Filaments Fractionation Gene expression Genes Genetic aspects Genomes Health aspects Hep G2 Cells Hepatitis B Hepatitis B virus - physiology Hepatitis Delta Virus - physiology Humans Immunofluorescence Immunoprecipitation Infections Intracellular Kinesin Kinesins - genetics Life cycles Liver cancer Localization Medicine and Health Sciences Methods Molecular targeted therapy Organic Anion Transporters, Sodium-Dependent - genetics Organic Anion Transporters, Sodium-Dependent - metabolism Patient outcomes Proteins Receptors Research and Analysis Methods Retinoid X receptors Retinoid X Receptors - agonists siRNA Symporters - genetics Symporters - metabolism Transfection Virus Internalization Viruses Japan
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Summary:	Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that can be therapeutically addressed using siRNA library transfection and HBV/NLuc (HBV/NL) reporter virus infection in HepG2-hNTCP cells. KIF4 silencing resulted in a 3-fold reduction in luciferase activity following HBV/NL infection. KIF4 knockdown suppressed both HBV and HDV infection. Transient KIF4 depletion reduced surface and raised intracellular NTCP (HBV/HDV entry receptor) levels, according to both cellular fractionation and immunofluorescence analysis (IF). Overexpression of wild-type KIF4 but not ATPase-null KIF4 mutant regained the surface localization of NTCP and significantly restored HBV permissiveness in these cells. IF revealed KIF4 and NTCP colocalization across microtubule filaments, and a co-immunoprecipitation study revealed that KIF4 interacts with NTCP. KIF4 expression is regulated by FOXM1. Interestingly, we discovered that RXR agonists (Bexarotene, and Alitretinoin) down-regulated KIF4 expression via FOXM1-mediated suppression, resulting in a substantial decrease in HBV-Pre-S1 protein attachment to HepG2-hNTCP cell surface and subsequent HBV infection in both HepG2-hNTCP and primary human hepatocyte (PXB) (Bexarotene, IC50 1.89 ± 0.98 μM) cultures. Overall, our findings show that human KIF4 is a critical regulator of NTCP surface transport and localization, which is required for NTCP to function as a receptor for HBV/HDV entry. Furthermore, small molecules that suppress or alleviate KIF4 expression would be potential antiviral candidates targeting HBV and HDV entry.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1009983