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. Author manuscript; available in PMC: 2019 Dec 19.
Published in final edited form as: Contact (Thousand Oaks). 2019 Dec 5;2:2515256419893507. doi: 10.1177/2515256419893507

Figure 1.

Figure 1

Proposed MCS interplay between LE/Lys with either ER or mitochondria for cholesterol egress from LE/Lys of NPC1 mutant cells. (a) Under normal conditions (wild type), LDL-cholesterol is internalized and delivered to LE/Lys. From there, LDL-derived cholesterol (yellow) is distributed/sorted mainly to the PM and the ER. Other less demanding destinations are mitochondria and the Golgi apparatus. In this setting, MCS between LE and ER are abundant and a significant number of LD for the storage of LDL-derived cholesteryl esters can be observed. The inset 1 illustrates some of the molecular partners on both sides of MCS, including Gramd1b which interacts with NPC1. (b) In the absence of NPC1, NPC1-tethered lysosome-ER contact sites are lost and cholesterol accumulates in the lysosome. Under these conditions, StARD3 mediates extended lysosome contact sites and cholesterol exchange with mitochondria (inset 2). Inset 4 shows the lack of NPC1 in the LE/Lys membrane and the untethering effect of AnxA6, which is recruited to LE/Lys in NPC1 mutant cells, promoting TBC1D15-mediated Rab7 inactivation (Rab7-GDP). As described by Höglinger et al. (2019), creating an artificial tether by overexpression of an ORP1L mutant, that cannot sense or transport sterol, but only expand ER-lysosome contacts, can establish cholesterol transport routes across MCS (inset 3). (c) Cholesterol transport to the ER in NPC1 mutant cells is restored upon AnxA6 depletion. Inset 5 illustrates the role of StARD3 transferring cholesterol from LE/Lys to the ER (in the direction of the cholesterol concentration gradient) across MCS. AnxA6 depletion leads to loss of TBC1D15-mediated Rab7 inactivation and consequently, upregulated Rab7 GTP levels. The implication of this increased Rab7-GTP in the formation or functioning of MCS is unknown. AnxA6 = Annexin A6; ER = endoplasmic reticulum; HDL = high-density lipoprotein; ILV = intraluminal vesicle; LD = lipid droplet; LDL = low-density lipoprotein; LE/Lys = late endosomal/lysosomal compartment; MCS = membrane contact sites; NPC1 = Niemann-Pick Type C1; PM = plasma membrane; mit = mitochondria.