Intertwined And Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, And Diseases Part 3

2.2.4. MCSs: Lipid Exchange

Newly synthesized lipids must be delivered from the lipid synthesis subdomains of the ER to their final destination. Each membrane-bound organelle has a specific lipid composition [107] and therefore lipid transfer requirements are tailored to each organelle. 

Lipids are an extremely important class of biomolecules that play a vital role in every aspect of our lives. In addition to their essential role in the composition of cell membranes, lipids are also closely linked to improved memory.

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Lipid composition affects many properties of an organelle membrane, including its curvature and the proteins recruited to both the cytoplasmic face of the organelle and the transmembrane proteins [108]. 

Lipids are known to be transported from the ER to other organelles via vesicular and non-vesicular transport mechanisms, such as lipid transfer proteins. Lipid transfer from the ER to the Golgi apparatus occurs via a vesicular mechanism, which forms part of the secretory pathway, and via monomolecular lipid transport mediated by lipid transfer proteins at the ER–Golgi interface. 

In the vesicular transport route, the membrane leaves the ER via ERES (Section 2.2.2) and the same vesicles/tubular-vesicular clusters that carry ER-synthesised proteins from the ER to the Golgi can also contain lipids metabolized in the ER [109]. These lipids then continue along the secretory pathway to reach their destination. Lipid transfer proteins traffic lipids between organelles that are not connected by vesicular transport pathways [83]. 

These transfer proteins are enriched at membrane contact sites between the ER and the plasma membrane [110–116], Golgi apparatus [117–119], and endosomes [120–125] (lipid transfer proteins at ER MCSs were recently reviewed in [108]). Evidence has recently been discovered for three-way MCSs between the ER, late endosomes, and mitochondria, via PDZD8, a protein that possesses a lipid transfer domain and interacts with protrudin, a key component for ER motility (Section 3.1.2), and Rab7 [126]. This three-way contact is hypothesized to facilitate lipid transfer between these three organelles. 

Contacts between the ER and late endosomes/lysosomes involve the ER-anchored VAP proteins (e.g., [82,127–129]), and these interactions are sensitive to nutrient status [128,129]. Importantly, contact sites between early endosomes and the ER in low cholesterol conditions facilitate the transfer of cholesterol from the ER to the multivesicular body, where it is needed to drive endosomal sorting via the formation of intraluminal vesicles (ILVs) [120]. 

As an aside, ER-early endosome contacts also facilitate ILV formation by providing sites where the ER-localised protein tyrosine phosphatase 1B dephosphorylates endocytosed, active growth factor receptors such as the epidermal growth factor receptor, which is required for EGFR to be sorted into ILVs [130]. This may be why motile early endosomes have been seen to pause at ER tubules [74]. 

Bidirectional cholesterol transfer also occurs at contacts between the ER and late endosomes/lysosomes (reviewed in [86,131]), and these sites involve several proteins implicated in recruiting microtubule motors (see below). Peroxisomes and the ER must exchange lipids as the synthesis of some lipids, for example, ether phospholipids, begins in peroxisomes but is completed in the ER [132,133]. 

The lipid transfer protein VPS13D has been discovered at both ER–peroxisome, and ER-mitochondria contacts, where it interacts with Miro [134], and another, VPS13A, has been found at ER-mitochondria contacts [124], and this lipid transport is important for peroxisome biogenesis [135]. The machinery involved in creating ER–peroxisome MCSs has recently been discovered [136] and there is some evidence for non-vesicular ER to peroxisome lipid transport [137]. 

Similarly, phosphatidylserine must be transferred from the ER, where it is synthesized, to the mitochondria, where it is converted to phosphatidylethanolamine [138–140]. It has been shown that this lipid transfer occurs even without cytosolic phospholipid exchange proteins or small vesicles [139,140] and is therefore likely to happen via lipid transfer proteins at ER-mitochondria MCSs. ERMES (ER-mitochondria encounter structure), a protein complex found in yeast, has been proposed as a tether-forming complex between the two organelles [141–144]. 

This complex may also transfer lipids at contact sites, via transport proteins such as Lam6/Ltc1. Lam6 interacts with the mitochondrial proteins Tom70 and Tom71 at ER–mitochondrial MCSs and is known to transfer sterols in vitro [145–147]. Likewise, PDZD8 may fulfill a similar role [126]. These non-vesicular pathways are a significant mechanism of lipid trafficking. 

Indeed, it was found that the rate of lipid transfer from the ER to the plasma membrane does not appreciably decrease when vesicular pathways are blocked [148–151], indicating that non-vesicular transport alone can sustain the required lipid transfer to the plasma membrane. 

As MCSs between the ER and other organelles, particularly the plasma membrane, mitochondria, and endosomes [73–78], preferentially form in the tubular ER network, these findings suggest that lipid transfer occurs primarily in the tubular ER.

2.2.5. MCSs: Calcium Control

Another important function of the ER is calcium ion sequestration and release. Ca2+ is an important signaling molecule, the concentration of which affects not only the function of the ER but also a wide range of other pathways, including mitochondrial metabolism and apoptosis [152–154]. 

Chaperone proteins within the ER such as calnexin [155], calreticulin [156], and protein disulfide isomerase [157], among others, bind to Ca2+ and their function as chaperones in protein folding is dependent on the calcium ion concentration in the ER [158,159]. The accumulation of improperly folded proteins leads to ER stress and activates the unfolded protein response (UPR), which can either restore ER homeostasis or induce apoptosis, depending on the cellular circumstances (reviewed in [160]). Therefore, regulation of Ca2+ concentration is imperative for normal cell function. 

Calcium ions are released from the ER by transmembrane receptors, primarily the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R), in response to intracellular cues. 

Mitochondria are located in positions close to IP3Rs [161,162] to take up Ca2+ ions upon their release. Calcium ions are necessary for mitochondrial metabolism, including ATP production and reduction of pyridine nucleotides [152,153]. To transfer Ca2+, a complex is formed between the ER-resident IP3R and voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane [161,163,164]. Grp75, a cytosolic protein, forms a tether between the channels to facilitate Ca2+ transfer to the mitochondria [165]. 

Mitofusin 2 is also implicated in both ER–mitochondrial tethering and mitochondrial calcium uptake [105], although there is some debate as to its exact role (reviewed in [166]). MCSs between the ER and mitochondria, which primarily occur in the tubular ER, are clearly of great importance for calcium ion homeostasis [85]. IP3Rs also mediate calcium transfer to lysosomes at ER–lysosome MCSs [167]. 

Upon ER calcium ion depletion, an influx of Ca2+ from extracellular sources is required to replenish the lumenal Ca2+ concentration. The transport of Ca2+ into the cell is accomplished by the cooperation of STIM1 and Orai1. 

After calcium stores have been depleted, the ERresident protein STIM1 [168] and the plasma membrane calcium channel, Orai1 [169], are recruited to ER-PM MCSs [170] where they form a complex [171]. Orai1 is a calcium release-activated calcium (CRAC) channel that is opened when the interaction with STIM1 occurs [172]. This process of Ca2+ influx is known as store-operated calcium entry (SOCE). 

The Ca2+ entering the cell is then transported into the ER via sarco/endoplasmic-reticulum Ca2+ ATPase (SERCA) pumps. These pumps expend ATP to transport calcium ions against the Ca2+ concentration gradient into the ER, refilling lumenal calcium stores [173–175]. 

From the work summarised here, it is apparent that MCSs with mitochondria and the plasma membrane are responsible for calcium ion release from the ER and influx from the extracellular region respectively. STIM1 also plays an important role in ER dynamics, by linking ER tubules to growing microtubules to form tip attachment complexes (TACs), as described in Section 3.1.3.

2.2.6. MCSs: Control of Membrane Fission and Fusion

A fascinating aspect of MCS function is that in several cases, they act as hotspots for membrane fission or fusion of the organelle bound to the ER. For example, mitochondrial fission occurs at points where they contact ER tubules and become constricted before the fission protein Drp1 is enriched [38,73]. 

Drp1 is always accumulated at, or next to, ER–ER-mitochondrial contacts. Interestingly, Drp1 has recently been shown to facilitate ER tubule formation and to be localized on all ER tubules at low levels, as well as generating sites for mitochondrial–ER interaction and mitochondrial fission [42]. However, this role in generating ER tubules does not require Drp10 s GTPase activity, which is essential for mitochondrial fission [42]. 

Mitochondrial fusion has also been shown to occur more frequently when mitochondria are attached to the ER [38]. As mentioned above, the ER also forms contacts with early endosomes, and these can also be the site of endosome fission [176]. 

One isoform of the microtubule-severing protein spastin localizes on the ER membrane, and it interacts with the early endosomal ESCRT protein IST1 at ER-early endosome contacts to drive endosomal tubule fission and sorting. Disrupting this interaction led to the missorting of lysosomal enzymes and lysosomal defects, which is likely to be the underlying reason why spastin mutations cause hereditary spastic paraplegia [177]. 

Another ER protein, reticulon 3L, has recently been shown to be recruited to ER–endosome contact sites by Rab9 and promote endosome maturation and sorting [178], likely explaining why endosome maturation correlates with enhanced interactions with the ER [75]. It will be interesting to determine if these are the same or different pathways. 

More than 90% of late endosomes/lysosomes are associated with the ER [38,179] and 80% of endosomal fission events happen when associated with the ER [176]. Retromer drives the sorting and recycling of material from the late endosome to the Golgi apparatus, and the scission of retromer tubules happens at points of contact with the ER and requires an ER membrane protein, TMCC1 that accumulates at ER–endosome contact sites, the actin-binding protein coronin 1 [179], and the WASH complex [127] and its interactor, strumpelin [177].

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