The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

Abstract

Rationale: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. Objective: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Methods and Results: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Conclusions: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.

LXR Regulation of Brain Cholesterol: From Development to Disease

“…The IDOL KO appeared to facilitate microglial clearance of Aβ, likely through permitting increased expression of LDLR that can act as a receptor for apoE, Aβ, or complexed apoE/Aβ species [30]. Recently a deubiquitylase, ubiquitin-specific protease 2 (USP2), has been reported to interact with IDOL and promote its deubiquitylation, which both stabilizes IDOL and decreases its ability to ubiquitylate the LDLR [31,32]. While USP2 expression did not appear to respond to LXR ligands, the participation of this protein indicates that the LXR-IDOL-LDLR pathway is part of a much larger and complex metabolic regulatory circuit that remains to be fully identified.…”

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

“…USP2, a member of the USP family, is widely expressed in organs, with relatively higher expression levels reported in the testis and skeletal muscle (Gousseva and Baker, 2003;Kitamura et al, 2013). It has diverse functions in a wide variety of cells, such as pro-and antiapoptotic effects in cancerous cells (Gewies and Grimm, 2003;Priolo et al, 2006), regulatory roles in cytokine production in macrophages (Zhang et al, 2014;Sun et al, 2016;Kitamura et al, 2017), and modulation of glucose and lipid metabolism (Molusky et al, 2012;Kitamura et al, 2013;Nelson et al, 2016;Saito et al, 2017). In a previous study, dominant negative forms of USP2 were found to interrupt the differentiation of L6 myoblasts into myofibers indicating the involvement of USP2 in myocyte differentiation (Park et al, 2002).…”

Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice

“…Furthermore, expression of USP2 in epithelial and breast cancer cells, and in the hypothalamus and cerebral cortex, has been shown to be modulated by adiponectin and hypoglycemia, respectively [24] , [25] . USP2 can also determine the turnover of low-density lipoprotein receptors in HepG2, A431, and HeLa cells [26] . These observations collectively indicate that USP2 is closely related to carbohydrate and lipid metabolism, and they thus highlight its regulatory roles in energy homeostasis.…”