The Ancient Origins of Death Domains Support the ‘Original Sin’ Hypothesis for the Evolution of Programmed Cell Death

La, So Ri; Ndhlovu, Andrew; Durand, Pierre M.

doi:10.1007/s00239-021-10044-y

Cited by 7 publications

(5 citation statements)

References 111 publications

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“…Interestingly, the presence of transmembrane domains is a widespread feature among orthocaspases and type-I MCAs in prokaryotes ( Klemenčič and Funk 2018 ; La et al 2022 ). Furthermore, transmembrane domains are predicted to occur (DeepTMHMM, Hallgren et al ., 2022 ), albeit with much lower frequency, in type-I MCAs from unicellular green algae, including A. protothecoides 0710 and Picochlorum sp.…”

Section: Discussionmentioning

confidence: 99%

Thermoprotection by a cell membrane–localized metacaspase in a green alga

Zou,

Sabljić,

Horbach

et al. 2023

The Plant Cell

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Caspases are restricted to animals, while other organisms, including plants possess metacaspases (MCAs), a more ancient and broader class of structurally related yet biochemically distinct proteases. Our current understanding of plant MCAs is derived from studies in streptophytes, and mostly in Arabidopsis (Arabidopsis thaliana) with nine MCAs with partially redundant activities. In contrast to streptophytes, most chlorophytes contain only one or two uncharacterized MCAs, providing an excellent platform for MCA research. Here we investigated CrMCA-II, the single type-II MCA from the model chlorophyte Chlamydomonas (Chlamydomonas reinhardtii). Surprisingly, unlike other studied MCAs and similar to caspases, CrMCA-II dimerizes both in vitro and in vivo. Furthermore, activation of CrMCA-II in vivo correlated with its dimerization. Most of CrMCA-II in the cell was present as a proenzyme (zymogen) attached to the plasma membrane (PM). Deletion of CrMCA-II by genome editing compromised thermotolerance, leading to increased cell death under heat stress. Adding back either wild-type or a catalytically dead CrMCA-II restored thermoprotection, suggesting that its proteolytic activity is dispensable for this effect. Finally, we connected the non-proteolytic role of CrMCA-II in thermotolerance to the ability to modulate PM fluidity. Our study reveals an ancient, MCA-dependent thermotolerance mechanism retained by Chlamydomonas and probably lost during the evolution of multicellularity.

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Section: Discussionmentioning

confidence: 99%

Thermoprotection by a cell membrane–localized metacaspase in a green alga

Zou,

Sabljić,

Horbach

et al. 2023

The Plant Cell

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“…The concept of programmed microbial death has been widely questioned in the last decade in part because authors did not use the same terminology to describe mechanistic and evolutionary cell death [17]. The mechanistic approach describing the complex biochemical machinery involved in cellular self-destruction is the most recognized approach in the field of mycology.…”

Section: Evidence For Candida Cell Deathmentioning

confidence: 99%

“…It includes figures that compare domain composition and biochemical characteristics between caspases, metacaspases, and paracaspases. Three types of metacaspases and two types of paracaspases have been described [17,49]. All homologous groups of caspases have the histidine-cysteine (HC) catalytic dyad on the p20-like region.…”

Section: Description Of Candida Metacaspasesmentioning

confidence: 99%

Specifically Targeting Metacaspases of Candida: A New Therapeutic Opportunity

Bienvenu,

Ballut,

Picot

2024

JoF

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The World Health Organization (WHO) recently published a list of fungal priority pathogens, including Candida albicans and C. auris. The increased level of resistance of Candida is raising concern, considering the availability of only four classes of medicine. The WHO is seeking novel agent classes with different targets and mechanisms of action. Targeting Candida metacaspases to control intrinsic cell death could provide new therapeutic opportunities for invasive candidiasis. In this review, we provide the available evidence for Candida cell death, describe Candida metacaspases, and discuss the potential of Candida metacaspases to offer a new specific target. Targeting Candida cell death has good scientific rationale given that the fungicidal activity of many marketed antifungals is mediated, among others, by cell death triggering. But none of the available antifungals are specifically activating Candida metacaspases, making this target a new therapeutic opportunity for non-susceptible isolates. It is expected that antifungals based on the activation of fungi metacaspases will have a broad spectrum of action, as metacaspases have been described in many fungi, including filamentous fungi. Considering this original mechanism of action, it could be of great interest to combine these new antifungal candidates with existing antifungals. This approach would help to avoid the development of antifungal resistance, which is especially increasing in Candida.

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“…Interestingly, the presence of transmembrane domains is a widespread feature among orthocaspases and type I MCAs in prokaryotes (Klemenčič and Funk, 2018;La et al, 2022).…”

Section: Pm Localization and Thermoprotective Role Of Crmca-iimentioning

confidence: 99%

Thermoprotection by a cell membrane-localized metacaspase in a green alga

Zou

Sabljić

Horbach

et al. 2023

Preprint

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Caspases are restricted to animals, while other organisms, including plants possess metacaspases (MCAs), - a more ancient and broader class of structurally-related proteases. Despite common structural fold, caspases and MCAs differ in substrate cleavage specificity and other biochemical properties, including strict requirement of dimerization for activation in caspases and proposed absence thereof in MCAs. Our current structure-function understanding of plant MCAs is derived from studies in streptophytes, and mostly in Arabidopsis thaliana expressing nine different MCAs with partly redundant and hence difficult to untangle, activities. In contrast to streptophytes, most chlorophyte genomes contain only one or two hitherto uncharacterized MCAs, providing powerful paradigms for evolutionary and mechanistic comprehension of MCAs. Here we investigate a single type II MCA CrMCA-II from a model chlorophyte Chlamydomonas reinhardtii. Unlike other studied MCAs, CrMCA-II dimerizes both in vitro and in vivo. While recombinant CrMCA-II is active in both monomeric and dimeric forms, activation of CrMCA-II in vivo correlates with the dimerization and autocleavage. Thus, the entire pool of CrMCA-II in vivo consists of monomers, dimers and, additionally, large megadalton complexes, with only dimers representing mature protease. Most of CrMCA-II in the cell is present as a zymogen attached to the plasma membrane (PM). Deletion of CrMCA-II by CRISPR/Cas9 compromises thermotolerance leading to increased cell death under heat stress. Adding back either wild-type or catalytically dead CrMCA-II restored thermoprotection, suggesting that its proteolytic activity is dispensable. Finally, we link the non-catalytic role of CrMCA-II in thermotolerance to the ability to modulate PM fluidity. Our study reveals an ancient, MCA-dependent thermotolerance mechanism retained by Chlamydomonas and probably lost during evolution of multicellularity.

show abstract

The Ancient Origins of Death Domains Support the ‘Original Sin’ Hypothesis for the Evolution of Programmed Cell Death

Cited by 7 publications

References 111 publications

Thermoprotection by a cell membrane–localized metacaspase in a green alga

Thermoprotection by a cell membrane–localized metacaspase in a green alga

Specifically Targeting Metacaspases of Candida: A New Therapeutic Opportunity

Thermoprotection by a cell membrane-localized metacaspase in a green alga

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