Membrane Fluidity Is Regulated Cell Nonautonomously byCaenorhabditis elegansPAQR-2 and Its Mammalian Homolog AdipoR2

Abstract

The properties of cell membranes are determined mostly by the types of fatty acids that they contain. Bodhicharla et al. report that a key regulator of membrane fluidity, the PAQR-2/IGLR-2 protein complex...

Membrane fluidity is regulated by the C. elegans transmembrane protein FLD-1 and its human homologs TLCD1/2

“…Expression of FLD-1::GFP in either hypodermis or intestine was also sufficient to restore the glucose intolerance of the paqr-2(tm3410) mutant, suggesting that fld-1 can act in a variety of tissues ( Figure 1—figure supplement 5A and C ). This is consistent with an earlier study demonstrating that the maintenance of membrane homeostasis is cell nonautonomous and may rely on effective trafficking of lipids among tissues ( Bodhicharla et al, 2018 ).…”

“…We have previously leveraged the power of forward genetics in the nematode C. elegans to demonstrate that the proteins PAQR-2 and IGLR-2 act as sensors in the plasma membrane that are essential to promote fatty acid desaturation and restore fluidity during cold adaptation or when fed diets rich in membrane-rigidifying saturated fatty acids (SFAs) ( Devkota et al, 2017 ; Svensk et al, 2016a ; Svensk et al, 2013 ; Svensson et al, 2011 ). Similarly, the human AdipoR1/2 that are homologs of the C. elegans PAQR-2, also regulate membrane fluidity in human cells ( Bodhicharla et al, 2018 ; Devkota et al, 2017 ). Given the importance of membrane homeostasis, we reasoned that other regulatory pathways likely exist to ensure its robust maintenance.…”

Leveraging a gain-of-function allele of Caenorhabditis elegans paqr-1 to elucidate membrane homeostasis by PAQR proteins

“…In eukaryotes, the SREBPs are regulated by the availability of specific lipids such as cholesterol in the ER membrane [8], PCYT1A is activated by association with packing defects in the inner nuclear membrane [9][10][11] and IRE1 is activated by multimerization in response to membrane thickening in the ER [1,12]. Recently we identified a novel regulator of membrane homeostasis in animal cells, namely the PAQR-2/IGLR-2 complex in the nematode C. elegans [13][14][15][16][17][18]. The present work helps define the structure-functional basis of fluidity sensing by this complex.…”

“…paqr-2 and iglr-2 single and double mutants have the same phenotypes, including a characteristic tail tip defect and intolerance to cold and dietary saturated fatty acids (SFAs) [16,31]. Additionally, the paqr-2 mutant, and presumably the iglr-2 mutant as well, also exhibits several phenotypes secondary to its primary membrane homeostasis defect, including defects in lifespan [30], vitellogenin trafficking [15], brood size [30], locomotion [30], autophagy [32] and proteostasis [33]. These phenotypes are secondary to the primary membrane fluidity defects of paqr-2 and iglr-2 mutants because they can be suppressed fully or partially by low, fluidizing concentrations of mild detergents [18], by providing supplements of unsaturated fatty acids [16,18], or by secondary mutations that increase the relative abundance of unsaturated fatty acids (UFAs) among phospholipids, such as mdt- 15 (et14), nhr- 49(et8), fld-1(et48) and several others [14,17,18].…”

“…PAQR-2 and IGLR-2 mostly act cell non-autonomously: expression in one large tissue (e.g. gonad sheath cells, intestine or hypodermis) is sufficient to rescue the entire worm; the one exception is the tail tip which requires local expression likely because it constitutes a site of poor lipid exchange with the rest of the worm [15]. Additionally, bifluorescence complementation (BiFC) showed that the proteins PAQR-2 and IGLR-2 interact with each other on the plasma membrane, and GFP reporters showed that they are both strongly expressed in the gonad sheath cells and weakly in many other tissues [17].…”