Heparan sulfate and clusterin: Cleaning squad for extracellular protein degradation

Sánchez‐Martín, Pablo; Komatsu, Masaaki

doi:10.1083/jcb.202001159

Cited by 3 publications

(4 citation statements)

References 8 publications

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“…Clusterin (CLU) is the 3rd strongest ERC of ACE2 and the ACE2-CLU pair show high reciprocal ranks to each other (3rd in ACE2’s set, 8th in CLU’s set). CLU prevents the aggregation of misfolded proteins in the blood and delivers them to cells for degradation in lysosomes ( Sánchez-Martín & Komatsu, 2020 ). CLU connects to key proteins in the coagulation pathway based on its reciprocal rank network (“ERC Reciprocal Rank Networks Implicate Coagulation Pathways and Immunity”, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Also relevant to coagulopathy are Clusterin (CLU) and the orphan G protein-coupled receptor 141 (GPR141). The chaperone protein CLU has a soluble form that circulates in the blood and is part of the “cleaning squad” that clears misfolded extracellular proteins for delivery to lysosomes and degradation ( Itakura et al, 2020 ; Sánchez-Martín & Komatsu, 2020 ). It is the 3rd highest ACE2 ERC (ρ = 0.63, FDR = 1.5E−04), and these two proteins show strong reciprocal ranks (3, 8), likely supporting biological interactions.…”

Section: Resultsmentioning

confidence: 99%

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Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Aa¹,

Cheng²,

Werren³

2021

PeerJ

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Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that “coevolve” with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Aa¹,

Cheng²,

Werren³

2021

PeerJ

View full text Add to dashboard Cite

show abstract

“…Clusterin (CLU) is the 3 rd strongest ERC of ACE2 and the ACE2-CLU pair show high reciprocal ranks to each other (3 rd in ACE2’s set, 8 th in CLU’s set). CLU prevents the aggregation of misfolded proteins in the blood and delivers them to cells for degradation in lysosomes (Sánchez-Martín & Komatsu, 2020). CLU connects to key proteins in the coagulation pathway based on its reciprocal rank network (Section C, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Also relevant to coagulopathy are Clusterin (CLU) and the orphan G protein-coupled receptor 141 (GPR141). The chaperone protein CLU has a soluble form that circulates in the blood and is part of the “cleaning squad” that clears misfolded extracellular proteins by delivery to lysosomes for degradation (Itakura, Chiba, Murata, & Matsuura, 2020; Sánchez-Martín & Komatsu, 2020). It is the 3 rd highest ACE2 ERC (ρ = 0.63, FDR = 1.5E-04), and these two proteins show strong reciprocal ranks (3, 8), likely supporting biological interactions.…”

Section: Resultsmentioning

confidence: 99%

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Cheng

Werren

2021

Preprint

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Angiotensin-converting enzyme 2 (ACE2) is the human cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken a different approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel interactors with ACE2 are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as coagulation factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). Additionally, ACE2 has connections to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible additional functions for well-characterized ones. Suggested validation approaches for ERC predicted ACE2 interacting proteins are discussed. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer

et al. 2022

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Heparan sulfate and clusterin: Cleaning squad for extracellular protein degradation

Cited by 3 publications

References 8 publications

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer

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