Gene Loss

Publication Details

Identifier: JB_QSGEJM

Curator: Raul Valente

DOI: 10.3389/fimmu.2021.747737

PMID: 34539677

Title:

Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures.

Abstract:

Programmed cell death is a vital process in the life cycle of organisms. Necroptosis, an evolutionary form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages, central components of necroptosis, such as RIPK3 and MLKL, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores' genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the N-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.

Last update:

07-01-2025

Associated Glosses (65 results)

GlossID	Species	Symbol	Gene Loss Mechanism	Loss Type	Lineage Specific	Citation
GL_RQATXC	Oryctolagus cuniculus algirus	MLKL	Gene deletion	Full	No	10.3389/fimmu.2021.747737
GL_RWSTD4	Lagenorhynchus obliquidens	MLKL	LOF (frameshift, premature stop, ss)	Full	Cetacea	10.3389/fimmu.2021.747737
GL_SGAZ6V	Trichechus manatus	RIPK3	LOF (frameshift, premature stop, ss)	Full	No	10.3389/fimmu.2021.747737
GL_TRNQNV	Lepus europaeus	RIPK3	LOF (frameshift, premature stop, ss)	Full	Leporidae	10.3389/fimmu.2021.747737
GL_TZBIEZ	Lepus granatensis	RIPK3	LOF (frameshift, premature stop, ss)	Full	Leporidae	10.3389/fimmu.2021.747737
GL_TZZPUD	Lepus americanus	MLKL	Gene deletion	Full	No	10.3389/fimmu.2021.747737
GL_U0QORS	Phocoena sinus	MLKL	LOF (frameshift, premature stop, ss)	Full	Cetacea	10.3389/fimmu.2021.747737
GL_UKSDZA	Lepus timidus	RIPK3	LOF (frameshift, premature stop, ss)	Full	Leporidae	10.3389/fimmu.2021.747737
GL_VHYAP7	Phocoena sinus	RIPK3	LOF (frameshift, premature stop, ss)	Full	No	10.3389/fimmu.2021.747737
GL_VI25Q9	Ochotona princeps	MLKL	Gene deletion	Full	No	10.3389/fimmu.2021.747737