Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7

Abstract

Plekha7 is a key adherens junction component involved in numerous functions in mammalian cells. Plekha7 is the most studied member of the PLEKHA protein family, which includes eight members with diverse functions. However, the evolutionary history of Plekha7 remains unexplored. Here, we outline the phylogeny and identify the origins of this gene and its paralogs. We show that Plekha7, together with Plekha4, Plekha5, and Plekha6, belong to a subfamily that we name PLEKHA4/5/6/7. This subfamily is distinct from the other Plekha proteins, which form two additional separate subfamilies, namely PLEKHA1/2 and PLEKHA3/8. Sequence, phylogenetic, exon-intron organization, and syntenic analyses reveal that the PLEKHA4/5/6/7 subfamily is represented by a single gene in invertebrates, which remained single in the last common ancestor of all chordates and underwent gene duplications distinctly in jawless and jawed vertebrates. In the latter species, a first round of gene duplications gave rise to the Plekha4/7 and Plekha5/6 pairs and a second round to the four extant members of the subfamily. These observations are consistent with the 1R/2R hypothesis of vertebrate genome evolution. Plekha7 and Plekha5 also exist in two copies in ray-finned fishes, due to the Teleostei-specific whole genome duplication. Similarities between the vertebrate Plekha4/5/6/7 members and non-chordate sequences are restricted to their N-terminal PH domains, whereas similarities across the remaining protein molecule are only sporadically found among few invertebrate species and are limited to the coiled-coil and extreme C-terminal ends. The vertebrate Plekha4/5/6/7 proteins contain extensive intrinsically disordered domains, which are topologically and structurally conserved in all chordates, but not in non-chordate invertebrates. In summary, our study sheds light on the origins and evolution of Plekha7 and the PLEKHA4/5/6/7 subfamily and unveils new critical information suitable for future functional studies of this still understudied group of proteins.

Actin-dependent recruitment of AGO2 to the zonula adherens

“…This analysis revealed that in addition to RNA-binding proteins, the set of PLEKHA7-associated proteins is significantly enriched for processes and functions related to the actin cytoskeleton ( Figure 1, A and B ). This result aligns with our previous findings that PLEKHA7 stabilizes apical actin and that it associates with certain actin-binding proteins ( Kourtidis et al. , 2015 ; Kourtidis and Anastasiadis, 2016 ).…”

“…, 2019 ; Ramirez Moreno and Bulgakova, 2021 ). Along these lines, we have previously demonstrated that cadherin junctions recruit core complexes of the RNA interference (RNAi) machinery, such as the microprocessor, the DICER complex, and the RNA-induced Silencing Complex (RISC), to locally regulate microRNA (miRNA) processing and function ( Kourtidis et al. , 2015 , 2017b).…”

“…, 2020 ). This recruitment was mediated by PLEKHA7 ( Kourtidis et al. , 2015 , 2017b; Nair-Menon et al.…”

“…, 2010 ). We have shown that loss of junctional AGO2 localization negatively impacts AGO2-loading of a specific set of miRNAs and several of their target oncogenic mRNAs, consequently releasing RISC-mediated oncogene suppression ( Kourtidis et al. , 2015 , 2017b).…”

Actin-dependent recruitment of AGO2 to the zonula adherens

“…A similar prediction can be made not only when referring to human epithelia, but also to epithelia from other species, especially when considering that we have already seen this localization in at least one more species (canine MDCK cells). Since we have shown that PLEKHA7 is vertebrate-specific and has no invertebrate ortholog (Kourtidis et al, 2022), it would be particularly interesting to examine whether junctional AGO2 exists in invertebrate species, for example by virtue of LMO7, which has invertebrate orthologs (Beati et al, 2018), or other similar actin-binding components. It remains to be seen whether these predictions will be confirmed in future studies.…”