RESUMO
Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness.
Assuntos
Retículo Endoplasmático/metabolismo , Ácidos Graxos/metabolismo , Membranas Intracelulares/metabolismo , Fluidez de Membrana , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Regulação Fúngica da Expressão Gênica , Proteínas de Membrana/química , Proteínas de Membrana/genética , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica em alfa-Hélice , Estabilidade Proteica , Proteólise , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Estearoil-CoA Dessaturase , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
Biological membranes are a defining feature of cellular life. They serve as selective diffusion barriers, compartmentalize biochemical processes and protect the cellular milieu. We are only beginning to understand the principles underlying their homeostasis and the functional relevance of their complex compositions. Here, we summarize some recent evidences that suggest an intense crosstalk between the pathways of protein quality control and lipid homeostasis. We discuss paradigms of lipid regulation by protein degradation machineries and highlight the intricate connections between lipid droplet morphology, membrane biogenesis and ER-stress.
