Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

Abstract

Cholesterol homeostasis is maintained through concerted action of the\r\nSREBPs and LXRs. Here, we report that RNF145, a previously\r\nuncharacterized ER membrane ubiquitin ligase, participates in crosstalk\r\nbetween these critical signaling pathways. RNF145 expression is induced\r\nin response to LXR activation and high-cholesterol diet feeding.\r\nTransduction of RNF145 into mouse liver inhibits the expression of genes\r\ninvolved in cholesterol biosynthesis and reduces plasma cholesterol\r\nlevels. Conversely, acute suppression of RNF145 via shRNA-mediated\r\nknockdown, or chronic inactivation of RNF145 by genetic deletion,\r\npotentiates the expression of cholesterol biosynthetic genes and\r\nincreases cholesterol levels both in liver and plasma. Mechanistic\r\nstudies show that RNF145 triggers ubiquitination of SCAP on lysine\r\nresidues within a cytoplasmic loop essential for COPII binding,\r\npotentially inhibiting its transport to Golgi and subsequent processing\r\nof SREBP-2. These findings define an additional mechanism linking\r\nhepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR\r\npathways.