Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Li, Li; Gómez, Antonio; Hakem, Razq

doi:http://dx.doi.org/10.1172/JCI120401

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Citation

Li L, Guturi KKN, Gautreau B, Patel PS, Saad A, Morii M et al. Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis. J Clin Invest. 2018; 128(10):4525-4542. DOI 10.1172/JCI120401

Abstract

Storage and consumption of neutral lipids in lipid droplets (LDs) are essential for energy homeostasis and tightly coupled to cellular metabolism. However, how metabolic cues are integrated in the life cycle of LDs is unclear. In this study, we characterize the function of Ldo16 and Ldo45, two splicing isoforms of the same protein in budding yeast. We show that Ldo proteins interact with the seipin complex, which regulates contacts between LDs and the endoplasmic reticulum (ER). Moreover, we show that the levels of Ldo16 and Ldo45 depend on the growth stage of cells and that deregulation of their relative abundance alters LD morphology, protein localization, and triglyceride content. Finally, we show that absence of Ldo proteins results in defects in LD morphology and consumption by lipophagy. Our findings support a model in which Ldo proteins modulate the activity of the seipin complex, thereby affecting LD properties. Moreover, we identify ER-LD contacts as regulatory targets coupling energy storage to cellular metabolism.