Inhibition of PIKFYVE kinase interferes ESCRT pathway to suppress RNA virus replication

Luo, Zhen; Liang, Yicong; Tian, Mingfu; Ruan, Zhihui; Su, Rui; Shereen, Muhammad Adnan; Yin, Jialing; Wu, Kailang; Guo, Jun; Zhang, Qiwei; Li, Yongkui; Wu, Jianguo

doi:10.1002/jmv.28527

Cited by 7 publications

(4 citation statements)

References 51 publications

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“…Instead, we had reported previously on the observation that phosphoinositides, specifically PI(3,4)P2 are displayed on LPVs [48]. Informed by studies that have identified PI (3,4)P2 and other phosphoinositides as membrane anchors for the recruitment of ESCRT components [42,44] we affirmed that LdLPVs do indeed display PI(3,4)P2, and then observed that treatment with LY294002 led to reduced display of this lipid and also reduced recruitment of CHMP4B to LdLPVs. The experiments with LY294002 were challenging because prolonged incubation of infected cells in this drug (greater than 8hrs) resulted in death of parasites and clearance from infected cells.…”

Section: Discussionsupporting

confidence: 58%

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Non canonical activation of the ESCRT machinery is required for division ofLeishmania donovaniparasitophorous vacuoles and parasite persistence

Rosero,

Kima

2024

Preprint

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In the mammalian host,L. donovaniare intracellular pathogens that reside in vacuolar compartments (often calledLeishmaniaparasitophorous vacuoles (LdLPVs)). LdLPVs harbor individual parasites that enigmatically divide upon replication of the parasite. In this study, we evaluated the role of the ESCRT machinery in the division of LdLPVs and parasite persistence in infected cells. We found that the ESCRT I member, TSG101 and the ESCRT III members, CHMP2B and CHMP4B are recruited to LdLPVs. In addition, Vps4a, an accessory molecule required for recycling of ESCRT III molecules is also recruited to LdLPVs. Interestingly, infection of cells expressing a dominant negative version of Vps4a that prevents the recycling of ESCRT III revealed that most LdLPVs recruit ESCRT components constitutively. Based on that finding, we proposed that the recruitment of ESCRT molecules to LdLPVs is enabled by the display of the phosphoinositide, PI(3,4)P2 on LdLPVs. To assess the functional importance of recruiting ESCRT molecules to LdLPVs, we monitoredL. donovaniinfections in cells in which ALIX or TSG101 were knocked down. ALIX knock down resulted in LdLPVs that were distended and harbored 4 or more parasites, which is significantly different from LdLPVs in ‘wild type’ macrophages that harbor at most, 2 parasites. Moreover, reduced levels of ALIX resulted in a significant reduction in parasite numbers. These findings revealed the critical role for activation of the ALIX-ESCRTIII axis inL. donovanipathogenesis. This is the first demonstration that the ESCRT machinery plays a role in the division of pseudo-organelles that harbor an intracellular pathogen.SignificanceThe endosomal sorting complex required for transport (ESCRT) machinery plays critical mechanistic roles in physiological processes including cell division (cytokinesis). It can be hijacked to promote the spread and persistence of infectious agents including in the budding of viruses and nutrient acquisition by intracellular pathogens. In this study, we uncover a new role for the ESCRT machinery in the infection of macrophages byLeishmania donovani(Ld). Within infected cells, each Ld parasite resides in aLeishmaniaparasitophorous vacuole (LPV) that enigmatically divides to accommodate daughter parasites. We show that a non-canonical activation of the ESCRT machinery is required for division of LPVs and for parasite persistence. Future studies on the mechanisms for selective activation of the ESCRT machinery would reveal targets for the control of this deadly pathogen.

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Section: Discussionsupporting

confidence: 58%

“…There is evidence that some phosphoinositide species are the membrane anchor to which ESCRT components are recruited [42][43][44]. It was shown that for the completion of cytokinesis, phosphoinositides serve as critical membrane anchors for ESCRT molecules ( [10,43].…”

Section: Introductionmentioning

confidence: 99%

Non canonical activation of the ESCRT machinery is required for division ofLeishmania donovaniparasitophorous vacuoles and parasite persistence

Rosero,

Kima

2024

Preprint

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“…We also found that inhibitors of host biology, including NAMPT, PIKfyve, and IMPDH, showed activity. PIKfyve inhibitors likely block viral entry ( 21 ). NAMPT inhibitors are very active but have toxicity concerns given their role in cellular energetics.…”

Section: Discussionmentioning

confidence: 99%

Nucleoside analogs NM107 and AT-527 are antiviral against rubella virus

et al. 2023

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Rubella is a highly contagious viral infection that usually causes a mild disease in children and adults. However, infection during pregnancy can result in a fetal or newborn death or congenital rubella syndrome (CRS), a constellation of permanent birth defects including cataracts, heart defects, and sensorineural deafness. The live-attenuated rubella vaccine has been highly effective with the Americas declared free of endemic rubella transmission in 2015. However, rubella remains a significant problem worldwide and the leading cause of vaccine-preventable birth defects globally. Thus, elimination of rubella and CRS is a goal of the World Health Organization. There exist no specific therapeutics approved for rubella virus. Therefore, we set out to identify whether existing small molecules may be repurposed for use against rubella virus infection. Thus, we performed a high-throughput screen for small molecules active against rubella virus in human respiratory cells and identified two nucleoside analogs, NM107 and AT-527, with potent antiviral activity. Furthermore, we found that combining these nucleoside analogs with inhibitors of host nucleoside biosynthesis had synergistic antiviral activity. These studies open the door to new potential approaches to treat rubella infections.

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“…After Professor Wu set up a lab at Wuhan University, China, he put extensive interests into human medical virology. Professor Wu and his group made fundamental progress in the mechanism of diverse viral infection, replication and pathogenesis, covering most common viruses [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ] and viral coinfections [ 17 , 18 , 19 , 20 ] in humans. In addition, Professor Wu devoted himself to mechanism research of viral-induced oncogenesis and exploring virus-based cancer therapeutic strategies.…”

mentioning

confidence: 99%