Co-conspirators in a new mechanism for the degradation of Δ9-desaturase

Abstract

Edited by Dennis R. Voelker ⌬9-Desaturases are central enzymes in unsaturated fatty acid synthesis regulated at the transcriptional and mRNA levels and by proteasomal degradation. A new study by Murakami et al. uncovers a novel regulatory pathway in which an N-terminal di-proline motif in the Drosophila ⌬9-desaturase mediates protein degradation by a calcium-dependent cysteine protease in response to unsaturated fatty acids. This study provides new details of desaturase regulation with therapeutic implications for the treatment of metabolic syndrome.⌬9-Desaturases are critical enzymes involved in unsaturated fatty acid metabolism in all living cells. They catalyze the synthesis of monounsaturated fatty acids (MUFAs), 2 mainly palmitoleate and oleate, from the corresponding saturated fatty acid substrates. MUFAs are important substrates for the synthesis of complex lipids including triglycerides, cholesterol esters, wax esters, and phospholipids (1). Moreover, the fatty acid composition of phospholipids in membranes modulates membrane fluidity, affecting a broad range of cellular and physiological functions. Given these important and wide-ranging roles for MUFAs, ⌬9-desaturases are regulated at multiple levels. However, none of the known regulatory mechanisms are directly responsive to changes in the levels of fatty acid desaturation among cellular lipids, raising the question as to how cells coordinate desaturase activity in response to changing environmental conditions. A new study by Murakami et al. (2) provides one answer with the discovery of a fatty acid saturation-sensitive pathway for protein degradation in Drosophila that surprisingly depends on a di-proline motif in the N-terminal region of the desaturase.The mechanisms underlying the regulation of fatty acid desaturase expression have been explored previously for both mammalian and yeast enzymes. For example, the mammalian desaturase, stearoyl-CoA desaturase 1 (SCD1), is regulated at the transcriptional level and by proteasome-mediated degradation while the yeast desaturase Ole1 is regulated at transcriptional and mRNA levels (3-5). While some of these mechanisms indirectly report on cellular lipid composition, such as in the transcriptional regulation of SCD1 by a master regulator of lipid biosynthesis (5), it is unknown whether lipid changes, monitored as either the lipid structures themselves or as influencing membrane properties more generally, might allow faster or otherwise complementary strategies to regulate desaturase activity. This is particularly relevant in Drosophila, which cannot synthesize sterols and contain only trace amounts of polyunsaturated fatty acids in membrane phospholipids (6), meaning small changes in unsaturated fatty acids could substantially alter the biophysical properties (i.e. fluidity) of membranes.In the study by Murakami et al. (2), the authors focus on the Drosophila enzyme DESAT1, the only desaturase expressed in the S2 cell line. Using a polyclonal antibody raised against a C-terminal peptide from the enzyme, the...

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