A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria

Lahiri, Sujoy; Chao, Jesse T.; Tavassoli, Shabnam; Wong, Andrew K.; Choudhary, Vineet; Young, Barry P.; Loewen, Christopher; Prinz, William A.

doi:10.1371/journal.pbio.1001969

Cited by 269 publications

(296 citation statements)

References 55 publications

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“…To estimate PS transport from the ER to mitochondria, we used a well-established assay that makes use of the fact that Psd1p, which converts PS to PE, is localized in the mitochondrial inner membrane (28,47). The conversion of PS to PE by Psd1p can be used to estimate the rate of PS transport to mitochondria in cells that lack Psd2p, which is outside mitochondria (24).…”

Section: Ps Synthesis At Er-mitochondria Contacts Enhances Ps Transpomentioning

confidence: 99%

Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER

Muthukumar

Lahiri

Liu

et al. 2017

Journal of Lipid Research

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Section: Ps Synthesis At Er-mitochondria Contacts Enhances Ps Transpomentioning

confidence: 99%

Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER

Muthukumar

Lahiri

Liu

et al. 2017

Journal of Lipid Research

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“…This adaptin mediates delivery of proteins to lysosome-related organelles in eukaryotes (18) and, in T. brucei, is localized to acidocalcisomes, Golgi, and late endosomes (19). We also identified five subunits of the conserved ER membrane complex or EMC, which plays a role in phospholipid transfer from the ER to mitochondria in yeast (20), but has not been characterized in T. brucei. Taken together, the outputs from our RNAi screen suggest an unexpected role for acidic compartments in sensitizing T. brucei to ISM.…”

Section: An Rnai Screen Implicates Acidic Compartments In Sensitizingmentioning

confidence: 99%

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

Baker

Hamilton

Wilkes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F 1 -γ-subunit of the two-sector F 1 F o -ATP synthase allow for F o -independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal F o -A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.brucei | mitochondrion | nagana | petite | samorin

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“…Emc6 contains a Rab5 interacting domain and has been shown to interact with Rab5A in humans during autophagosome formation ( Li et al , 2013). It has also been shown that the EMC is an ER-mitochondria tether in S. cerevisiae that interacts with the outer membrane protein Tom5 of the TOM (Translocase of the Mitochondrial Outer Membrane) complex ( Lahiri et al , 2014). Most recently, the EMC has been implicated in the proper assembly of multi-pass transmembrane (TM) proteins ( Satoh et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

“…However, ERMES as an ER-mitochondria tether is limited to a subset of eukaryote taxa ( Wideman et al , 2013), suggesting that a universal ER-mitochondria tethering complex might exist. Lahiri et al (2014) state in their title that the EMC is a conserved protein complex. However, by stating that a protein is conserved, cell biologists and biochemists often simply mean that the protein is present in S. cerevisiae (fungi) and animals.…”

Section: Introductionmentioning

confidence: 99%

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

Wideman

2015

F1000Res

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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.

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A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria

Abstract: Tethering of the endoplasmic reticulum to mitochondria by a conserved endoplasmic reticulum complex is needed for the transfer of phospholipids between these organelles.

Cited by 269 publications

References 55 publications

Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER

Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER

Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes

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

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