Lysosomal Ion Channels as Decoders of Cellular Signals

Li, Ping; Gu, Mingxue; Xu, Haoxing

doi:10.1016/j.tibs.2018.10.006

Cited by 129 publications

(139 citation statements)

References 104 publications

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“…These results suggested that PIKfyve might be a potential general drug target for viruses that enter cells through endocytosis. Two pore channel subtype 2 (TPC2) and TRPML1 in lysosome are two major downstream effectors of PI(3,5)P 2 36 . While blocking TPC2 activity by tetrandrine, an inhibitor for TPC2 37 , decreased entry of SARS-CoV-2 S pseudovirions ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

et al. 2020

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Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2. 1 1234567890():,;C oronaviruses (CoVs) infect human and animals and cause varieties of diseases, including respiratory, enteric, renal, and neurological diseases 1 . They are classified into four genera, alpha-CoV, beta-CoV, gamma-CoV, and delta-CoV 2 . Since beginning of this century, there have already been three zoonotic outbreaks of beta-CoVs. In 2002-2003, severe acute respiratory syndrome coronavirus (SARS-CoV) 3,4 , a lineage B beta-CoV, emerged from bat and palm civet 5,6 , and infected over 8000 people and caused about 800 deaths 7 . In 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), a lineage C beta-CoV, was discovered as the causative agent of a severe respiratory syndrome in Saudi Arabia 8 , currently with 2494 confirmed cases and 858 deaths 9 , it remains endemic in Middle East, and dromedary camel is considered as the zoonotic reservoir host of MERS-CoV. At the end of 2019, a novel coronavirus, named SARS-CoV-2, was found in patients with severe pneumonia in Wuhan, China 10-12 . Viruses were isolated from patients and sequenced. Phylogenetical analysis revealed that it is a lineage B beta-CoV and closely related to a SARS-like (SL) CoV, RaTG13, discovered in a cave of Yunnan, China, in 2013 13 . They share about 96% nucleotide sequence identities, suggesting that SARS-CoV-2 might have emerged from a Bat SL-CoV. However, the intermediate host or whether there is an intermediate host remains to be determined.CoV uses its spike glycoprotein (S), a main target for neutralization antibody, to bind its receptor, and mediate membrane fusion and virus entry. Each monomer of trimeric S protein is about 180 kDa, and contains two subunits, S1 and S2, mediating attachment and membrane fusion, respectively. In the structure, N-and C-terminal portions of S1 fold as two independent domains, N-terminal domain (NTD) and C-terminal domain (C-domain) (Fig. 1a). Depending on the virus, either NTD or Cdomain can serve as the receptor-binding domain (RBD). While RBD of mouse hepatitis virus (MHV) is located at the NTD 14 , most of other CoVs, including SARS-CoV and MERS-CoV use C-...

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Section: Resultsmentioning

confidence: 99%

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

et al. 2020

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“…These results suggested that PIKfyve might be a potential general drug target for viruses that enter cells through endocytosis. Two pore channel subtype 2 (TPC2) and TRPML1 in lysosome are two major downstream effectors of PI(3,5)P 2 35 . While blocking TPC2 activity by tetrandrine, a inhibitor for TPC2 36 , significantly decreased entry of 2019-nCoV S pseudovirions ( Fig 3F), treatment of cells with 130, a TRPML1 inhibitor, had no effect ( Fig S1), indicating that TPC2, not TRPML1, is important for 2019-nCoV entry.…”

Section: Resultsmentioning

confidence: 99%

Characterization of spike glycoprotein of 2019-nCoV on virus entry and its immune cross-reactivity with spike glycoprotein of SARS-CoV

Liu

Lei

et al. 2020

Preprint

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Since beginning of this century, there have already been three zoonotic outbreaks caused by beta coronaviruses (CoV), SARS-CoV in 2002, MERS-CoV in 2012, and the newly identified 2019-nCoV in late 2019, Wuhan, China. As to Feb 10 th , 2020, there are over 40,000 confirmed cases and over 900 deaths. However, little is known about the biology of this newly emerged virus. Here we developed a lentiviral based pseudovirus system for S protein of 2019-nCoV to study virus entry in BSL2 settings. First, we confirmed that human angiotensin converting enzyme 2 (hACE2) is the main entry receptor for 2019-nCoV.Second, we found that 2019-nCoV S protein mediated entry on 293/hACE2 cells was mainly through endocytosis, and PIKfyve, TPC2, and cathepsin L are critical for virus entry. Third, 2019-nCoV S protein is less stable than SARS-CoV, and it could trigger proteaseindependent and receptor dependent cell-cell fusion, which might help virus rapidly spread from cell to cell. Finally and more importantly, polyclonal anti-SARS S1 antibodies T62 effectively inhibited entry of SARS-CoV S pseudovirions, but almost had no effect on entry of 2019-nCoV S pseudovirions. Further studies using sera from one recovered SARS-CoV patient and five 2019-nCoV patients showed that there was only limited crossneutralization activities between SARS-CoV and 2019-nCoV sera, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for 2019-nCoV.

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“…Transient receptor potential canonical (TRPC) is a calcium channel protein, which can be transported to intracellular [Ca 2+ ], involved in the regulation of cell proliferation, differentiation, and various physiological functions. In addition, the TRPC activation increased intracellular [Ca 2+ ] through the regulation of nicotinamide‐adenine dinucleotide phosphate (NADPH) oxidase, inducible nitric oxide synthase (iNOS), and mitochondrial metabolism process to generate intracellular excessive ROS that result in intracellular high oxidative stress . Clinical studies pointed out that gene or protein expressions of TRPC3 and TRPC6 are abnormally elevated in the blood of diabetics .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the TRPC activation increased intracellular [Ca 2+ ] through the regulation of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, inducible nitric oxide synthase (iNOS), and mitochondrial metabolism process to generate intracellular excessive ROS that result in intracellular high oxidative stress. 6,7 Clinical studies pointed out that gene or protein expressions of TRPC3 and TRPC6 are abnormally elevated in the blood of diabetics. 8 However, the role of TRPC in diabetes mellitus is still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Novel findings of 18β‐glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high‐glucose environment

Tung

Chen

et al. 2019

BioFactors

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Enhancing soluble receptor for advanced glycation endproducts (sRAGE) is considered as a potent strategy for diabetes therapy. sRAGE secretion is regulated by calcium and transient receptor potential canonical (TRPC) channels. However, the role of TRPC channels in diabetes remains unknown. 18β‐Glycyrrhetinic acid (18β‐GA), produced from liquorice, has shown antidiabetic properties. This study was aimed to investigate the effect of 18β‐GA on sRAGE secretion via TRPC channels in high glucose (HG)‐induced THP‐1 cells. HG treatment enhanced TRPC3 and TRPC6 expression and consequently caused reactive oxygen species (ROS) accumulation mediated through p47 nicotinamide‐adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) associated with uncoupling protein 2 (UCP2) decline and lower sRAGE secretion. Interestingly, 18β‐GA showed the dramatic effects similar to Pyr3 or 2‐aminoethyl diphenyl borinate inhibitors and effectively reversed HG‐elicited mechanisms including that blocking TRPC3 and TRPC6 protein expressions, suppressing intracellular [Ca2+] concentration, decreasing expressions of ROS, p47s, and iNOS, but increasing UCP2 level and promoting sRAGE secretion. Therefore, 18β‐GA provides a potential implication to diabetes mellitus and its complications.

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Lysosomal Ion Channels as Decoders of Cellular Signals

Cited by 129 publications

References 104 publications

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Characterization of spike glycoprotein of 2019-nCoV on virus entry and its immune cross-reactivity with spike glycoprotein of SARS-CoV

Novel findings of 18β‐glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high‐glucose environment

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