Sterol uptake by the NPC system in eukaryotes: a Saccharomyces cerevisiae perspective

Abstract

Sterols are an essential component of membranes in all eukaryotic cells and the precursor of multiple indispensable cellular metabolites. After endocytotic uptake, sterols are integrated into the lysosomal membrane by the Niemann-Pick type C (NPC) system before redistribution to other membranes. The process is driven by two proteins that, together, compose the NPC system: the lysosomal sterol shuttle protein NPC2 and the membrane protein NPC1 (named NCR1 in fungi), which integrates sterols into the lysosomal membrane. The Saccharomyces cerevisiae NPC system provides a compelling model to study the molecular mechanism of sterol integration into membranes and sterol homeostasis. This review summarizes recent advances in the field, and by interpreting available structural data, we propose a unifying conceptual model for sterol loading, transfer and transport by NPC proteins.

Heterologous expression of MiMLDP, a major lipid droplet protein of the microalga Myrmecia incisa, in Saccharomyces cerevisiae promotes more triacylglycerol storage principally by enlarging lipid droplet size

“…That is to say, the synthesis of steryl esters has been found by Connerth et al (2010) to be strongly inhibited by oleic acid, thus leading to a reduction of steryl esters in LDs. In both of these cases, the reduced steryl esters from the neutral lipids rationally accompanies with the concentration of free sterols in membranes to which the amphiphilic nature of sterols con nes (Winkler et al 2022), if MiMLDP also prevents LDs from synthesizing steryl esters. The participation of excess sterols in membranes is thereby assumed to be responsible for the expansion of LD membranes, though the experimental data remains to be obtained.…”

Functional analysis of a NPC1 gene from the whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae)

“…Therefore, insects must obtain sterols from their diets, and this takes place in the digestive tract of insects, the organ for nutrient absorption (Li & Jing, 2020). The molecular mechanism underlying sterol absorption and transportation is still not fully understood in insects, but there are some key players identified, including the Niemann‐Pick C1 (NPC1) (Winkler et al, 2022).…”

“…The molecular mechanism underlying sterol absorption and transportation is still not fully understood in insects, but there are some key players identified, including the Niemann-Pick C1 (NPC1) (Winkler et al, 2022).…”

Conformational changes in the Niemann-Pick Type C1 protein NCR1 drive sterol translocation

“…A mechanistic model for sterol transport through the tunnel, as well as energy requirements, including possible coupling to the transmembrane proton gradient, remain unclear. It is also unclear if NTD loading and transfer in the NPC proteins are rigidly coupled to their transport cycle, or whether the NTD functions independently of the RND core domains (SSD + MLD and pSSD + CTD) (Winkler et al, 2022).…”

“…Niemann Pick Type C1 (NPC1) membrane proteins are critical for establishing cell sterol homeostasis in eukaryotes. Sterols are typically transported via the endocytic pathway to acidic organelles (lysosomes and vacuoles) before integration via NPC1 into the membrane for further redistribution (Winkler et al, 2022). Failure to integrate sterols into the membrane leads to lipid accumulation in lysosomes and in humans gives rise to a neurodegenerative lysosomal storage disorder called NPC disease (Evans & Hendriksz, 2017; Ribeiro et al, 2001).…”