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. 2023 May 10;12(10):1353. doi: 10.3390/cells12101353

Figure 1.

Figure 1

The nuclear hormone receptor NHR-49 functions downstream of the membrane fluidity sensor PAQR-2 and the AMP-activated protein kinase (AMPK) to promote membrane fluidity. (a) PAQR-2 and its binding partner IGLR-2, which is a transmembrane protein, act as sensors for low membrane fluidity caused by cold exposure or dietary saturated fatty acids (SFAs). In a proposed model by Busayavalasa and colleagues, PAQR-2′s regulatory domain blocks access to the catalytic site of PAQR-2 in fluidized membrane conditions (i) [63]. Rigidification and thickening of the membrane stabilize the interaction of PAQR-2 with IGLR-2, which, in turn, results in a displacement of the regulatory domain and enables access of a PAQR-2 substrate to PAQR-2′s catalytic site (ii). PAQR-2 has a putative ceramidase activity and might catalyze ceramides to sphingosines. It still needs to be determined whether sphingosine 1-phosphate (S1P), which is generated by the phosphorylation of sphingosine, induces NHR-49. NHR-49 associates with MDT-15 and promotes ∆9 desaturase expression and membrane fluidity. The model for PAQR-2′s membrane-sensing function was adapted from Busayavalasa and colleagues [63,68]. (b) A glucose-restricted diet activates a neuronal AMPK variant, resulting in neuropeptide release and activation of NHR-49. NHR-49 function requires PAQR-2 activity in a glucose-restricted dietary regimen to induce membrane fluidity via ∆9 desaturases [69]. Red-colored phospholipids indicate phospholipids with double bonds in their acyl chains. PAQR-2, progestin and adipoQ receptor-like protein; IGLR-2, immunoglobulin domain and leucine-rich repeat-containing protein 2; NHR-49, nuclear hormone receptor-49; MDT-15, subunit of the Mediator complex; PL, phospholipids; UFA, unsaturated fatty acids.