The ubiquitous and ancient ER membrane protein complex (EMC): tether or not?

Abstract

The recently discovered endoplasmic reticulum (ER) membrane protein complex (EMC) has been implicated in ER-associated degradation (ERAD), lipid transport and tethering between the ER and mitochondrial outer membranes, and assembly of multipass ER-membrane proteins. The EMC has been studied in both animals and fungi but its presence outside the Opisthokont clade (animals + fungi + related protists) has not been demonstrated. Here, using homology-searching algorithms, I show that the EMC is truly an ancient and conserved protein complex, present in every major eukaryotic lineage. Very few organisms have completely lost the EMC, and most, even over 2 billion years of eukaryote evolution, have retained a majority of the complex members. I identify Sop4 and YDR056C in Saccharomyces cerevisiae as Emc7 and Emc10, respectively, subunits previously thought to be specific to animals. This study demonstrates that the EMC was present in the last eukaryote common ancestor (LECA) and is an extremely important component of eukaryotic cells even though its primary function remains elusive.

Giardia intestinalis mitosomes undergo synchronized fission but not fusion and are constitutively associated with the endoplasmic reticulum

“…However, the function of this interaction has recently been questioned [16]. Importantly, all these structures have limited evolutionary distributions and none of them is present in metamonads, including G. intestinalis [60, 61]. In addition, several proteins are enriched in the so-called mitochondria-associated membranes (MAMs), a specific region of the ER, which comes into contact with mitochondria and mainly accommodates lipid and fatty acid metabolic enzymes [62].…”

“…The complete set of four ERMES components can be found across all supergroups of eukaryotes, although is missing in most Excavata species [60]. The EMC is more conserved among eukaryotes, but it is missing in all metamonads including G. intestinalis and Trichomonas vaginalis [61]. Considering that both the ERMES and the EMC were likely present in the last eukaryotic common ancestor (LECA), it is highly probable that they were lost in G. intestinalis and perhaps all metamonads.…”

Squaring the EMC – how promoting membrane protein biogenesis impacts cellular functions and organismal homeostasis

“…The EMC was first described as an integral membrane protein complex in yeast, with similar genetic interaction patterns and whose six protein products co-precipitated as a hetero-oligomer (Jonikas et al, 2009). Two other membrane proteins, SOP4 and YDR056C, also co-purified with this complex (Jonikas et al, 2009) and would later be re-classified as EMC7 and EMC10, respectively, to yield a mature complex of at least eight subunits (Wideman, 2015). An MS-based mapping of the ER-associated degradation (ERAD) interaction network not only confirmed the EMC orthologue in mammals but also identified EMC8 and EMC9, two metazoan-specific subunits that share over 40% sequence identity (Christianson et al, 2012).…”

“…Several years later, the mammalian orthologue was independently identified using mass spectrometry (MS) through links to ER quality control components (Christianson et al, 2012). The EMC is evolutionarily conserved, with origins reaching back to the last eukaryotic common ancestor (LECA) (Wideman, 2015). An ancient heritage reflects strong positive selection throughout evolution to retain the EMC and the cellular function(s) it performs.…”

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers ofC9orf72dipeptide repeat protein toxicity

“…We also identified genes involved in RNA-splicing such as SPEN and PQBP1, a process previously observed to be dysregulated in C9FTD/ALS patient brains (26) and dramatically disrupted in human cell lines treated with DPRs (9). In addition to these previously implicated genes, some of the strongest hits in the screen were genes encoding ER-resident proteins, such as TMX2, CANX, almost all members of the endoplasmic reticulum membrane protein complex (EMC), a complex that is upregulated by ER stress and is thought to be involved in ER-associated degradation (ERAD) (27)(28)(29), and genes encoding proteasome subunits. Chromatin modifiers and transcriptional regulators, including genes involved in histone lysine methylation (KDM6A, KMT2D, KMT2A, and SETD1B) were also significant genetic modifiers of PR and GR toxicity.…”