Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway

Lee, Na Rae; Park, Beom Seok; Kim, Seong Yeol; Gu, Ayoung; Kim, Da Hye; Lee, Ji-Sook; Kim, In Sik

doi:10.1016/j.cyto.2016.07.005

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…Inhibition of MAP kinase p38 was accomplished with SB202190 (evaluated previously in Leishmania infections, Ruhland et al, ). Toll‐like receptor 4 (TLR4)‐dependent signalling was inhibited with CLI‐095, which also inhibits ERK and JNK map kinase (Lee et al, ). As shown in Figure c, neither CLI‐095 nor SP202190 resulted in reduced levels of Akt phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

Zhang

Prasad

Despointes

et al. 2018

Cellular Microbiology

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Miltefosine is an important drug for the treatment of leishmaniasis; however, its mechanism of action is still poorly understood. In these studies, we tested the hypothesis that like in cancer cells, miltefosine's efficacy in leishmaniasis is due to its inhibition of Akt activation in host cells. We show using pharmacologic agents that block Akt activation by different mechanisms and also using an inducible knockdown approach that miltefosine loses its efficacy when its access to Akt1 is limited. Interestingly, limitation of Akt activation results in clearance of established Leishmania infections. We then show, using fluorophore-tagged probes that bind to phosphoinositides, that Leishmania parasitophorous vacuole membranes (LPVMs) display the relevant phosphoinositides to which Akt can be recruited and activated continuously. Taken together, we propose that the acquisition of PI(4) P and the display of PI (3,4)P2 on LPVMs initiate the machinery that supports continuous Akt activation and sensitivity to miltefosine.

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Section: Resultsmentioning

confidence: 99%

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

Zhang

Prasad

Despointes

et al. 2018

Cellular Microbiology

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“…The intrinsic pathway-specific apoptosome is assembled to participate in recruiting and processing procaspase-9 [28]. Eventually, processed caspase-9 activates the downstream caspases-3, -6, and -7, which leads to cell apoptosis [29]. …”

Section: Overview Of Apoptosismentioning

confidence: 99%

Differential Impacts of Alternative Splicing Networks on Apoptosis

Lin

Tsao

Lin

2016

IJMS

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Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases.

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“…As a homodimer, A9 potently activates inflammation via Toll-like receptor 4 (TLR4). [18][19][20][21][22][23][24][25][26][27][28][29][30] As a heterocomplex with S100A8 (A8/A9, also known as calprotectin), it is antimicrobial (Figure 1a). [31][32][33][34][35][36][37][38][39][40][41][42][43][44] A9 exacerbates endotoxin-induced shock in mice.…”

Section: Introductionmentioning

confidence: 99%

Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

Harman

Loes

Warren

et al. 2020

eLife

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Multifunctional proteins are evolutionary puzzles: how do proteins evolve to satisfy multiple functional constraints? S100A9 is one such multifunctional protein. It potently amplifies inflammation via Toll-like receptor four and is antimicrobial as part of a heterocomplex with S100A8. These two functions are seemingly regulated by proteolysis: S100A9 is readily degraded, while S100A8/S100A9 is resistant. We take an evolutionary biochemical approach to show that S100A9 evolved both functions and lost proteolytic resistance from a weakly proinflammatory, proteolytically resistant amniote ancestor. We identify a historical substitution that has pleiotropic effects on S100A9 proinflammatory activity and proteolytic resistance but has little effect on S100A8/S100A9 antimicrobial activity. We thus propose that mammals evolved S100A8/S100A9 antimicrobial and S100A9 proinflammatory activities concomitantly with a proteolytic ‘timer’ to selectively regulate S100A9. This highlights how the same mutation can have pleiotropic effects on one functional state of a protein but not another, thus facilitating the evolution of multifunctionality.

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Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway

Cited by 15 publications

References 33 publications

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

Differential Impacts of Alternative Splicing Networks on Apoptosis

Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9

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