Evolutionary history and origin of Tre1 superfamily shed light on its role in regulating blood brain barrier

Kubick, Norwin; Klimovich, Pavel; Bieńkowska, Irmina; Sacharczuk, Mariusz; Mickael, Michel‐Edwar

doi:10.1101/2021.04.29.441935

Cited by 3 publications

References 27 publications

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Fezf2 and Aire1 evolutionary trade-off in negative selection of T cells in the thymus

Mickael

Kubick

Gurba

et al. 2022

Preprint

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In vertebrates, thymus expression of various body proteins to eliminate autoreactive T cells during the negative selection process is orchestrated by AIRE and FEZF2. T cells first appeared in vertebrates. However, the evolutionary history of these two genes in relation to T cells emergence is still not clear. Specifically, it is still not known, whether these two genes emerged concurrently to support the negative selection process. Furthermore, whether there is an evolutionary trade-off between these two genes is not known. Whether these two genes play a similar role in controlling auto-reactivity elimination in lampreys and invertebrates is also unknown. We used a plethora of phylogenetic analysis tools including; multiple sequence alignment, phylogenetic tree building, ancestral sequence reconstruction, functional specificity investigation, and positive selection analysis to address these questions. We found that these two genes represent two distinct pathways of negative selection with two unique origins. While AIRE emerged during the divergence of T cells in vertebrates, FEZF2 is far ancient with homologs in invertebrates including Cnidaria, Trichoplax. We found that FEZF2 structure is highly conserved between invertebrates and vertebrates. Moreover, the genes controlled by both families included a mixture of ancient and recently diverged genes. However, we found that AIRE contains an LXXLL motif for binding nuclear receptors. Conversely, FEZF2 possesses several motifs known to play a role in autophagy, such as DKFPHP, SYSELWKSSL, and SYSEL. However, both genes contain similar motifs such as MAPK regulating motifs. Interestingly, AIRE seems to be lacking in lampreys, in contrast to FEZF2. Taken together, our investigation hints that FEZF2 was initially employed to control a rudimentary auto-reactivity elimination process in invertebrates, then evolved to play a part in controlling a negative selection process in early vertebrates and higher vertebrates. The emergence of AIRE seems to be correlated with controlling the negative selection process in higher vertebrates. The results demonstrate a strong evolutionary trading-off process, where FEZF2 kept controlling certain biological processes whereas AIRE gained control of others. Several critical genes are controlled by both genes, to ensure an adequate negative selection process.

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Fezf2 and Aire1 evolutionary trade-off in negative selection of T cells in the thymus

Mickael

Kubick

Gurba

et al. 2022

Preprint

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Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation

Kubick¹,

Paszkiewicz

Bieńkowska³

et al. 2023

IJMS

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The MCC family of genes plays a role in colorectal cancer development through various immunological pathways, including the Th17/Treg axis. We have previously shown that MCC1 but not MCC2 plays a role in Treg differentiation. Our understanding of the genetic divergence patterns and evolutionary history of the MCC family in relation to its function, in general, and the Th17/Treg axis, in particular, remains incomplete. In this investigation, we explored 12 species’ genomes to study the phylogenetic origin, structure, and functional specificity of this family. In vertebrates, both MCC1 and MCC2 homologs have been discovered, while invertebrates have a single MCC homolog. We found MCC homologs as early as Cnidarians and Trichoplax, suggesting that the MCC family first appeared 741 million years ago (Ma), whereas MCC divergence into the MCC1 and MCC2 families occurred at 540 Ma. In general, we did not detect significant positive selection regulating MCC evolution. Our investigation, based on MCC1 structural similarity, suggests that they may play a role in the evolutionary changes in Tregs’ emergence towards complexity, including the ability to utilize calcium for differentiation through the use of the EFH calcium-binding domain. We also found that the motif NPSTGE was highly conserved in MCC1, but not in MCC2. The NPSTGE motif binds KEAP1 with high affinity, suggesting an Nrf2-mediated function for MCC1. In the case of MCC2, we found that the “modifier of rudimentary” motif is highly conserved. This motif contributes to the regulation of alternative splicing. Overall, our study sheds light on how the evolution of the MCC family is connected to its function in regulating the Th17/Treg axis.

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Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

Konsman

2022

Pharmaceuticals

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In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, peripheral infection-induced systemic inflammation can also be accompanied by increased cerebral cytokine production. Furthermore, it has been recently proposed that some forms of psychological stress may have similar CNS effects. Different conditions of cerebral cytokine production and action will be reviewed here against the background of neuroinflammation. Within this context, it is important to both deepen our understanding along already taken paths as well as to explore new ways in which neural functioning can be modified by cytokines. This, in turn, should enable us to put forward different modes of cerebral cytokine production and action in relation to distinct forms of neuroinflammation.

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Evolutionary history and origin of Tre1 superfamily shed light on its role in regulating blood brain barrier

Cited by 3 publications

References 27 publications

Fezf2 and Aire1 evolutionary trade-off in negative selection of T cells in the thymus

Fezf2 and Aire1 evolutionary trade-off in negative selection of T cells in the thymus

Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation

Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

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