E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis

Abstract

Chronic low-grade inflammation orchestrated by macrophages plays a critical role in metabolic chronic diseases, like obesity and atherosclerosis. However, the underlying mechanism remains to be elucidated. Here, the E3 ubiquitin ligase F-box/WD Repeat-Containing Protein 2 (FBXW2), the substrate-binding subunit of E3 ubiquitin ligase SCF (a complex of FBXW2, SKP1, and cullin-1), as an inflammatory mediator in macrophages, is identified. Myeloid-specific FBXW2 gene deficiency improves both obesity-associated with insulin resistance and atherosclerosis in murine models. The beneficial effects by FBXW2 knockout are accompanied by decreased proinflammatory responses and macrophage infiltration in the microenvironment. Mechanistically, it is identified that KH-type splicing regulatory protein (KSRP) is a new bona fide ubiquitin substrate of SCF FBXW2. Inhibition of KSRP prevents FBXW2-deficient macrophages from exerting a protective effect on inflammatory reactions, insulin resistance and plaque formation. Furthermore, it is demonstrated that the C-terminus (P3) of FBXW2 competitively ablates the function of FBXW2 in KSRP degradation and serves as an effective inhibitor of obesity and atherogenesis progression. Thus, the data strongly suggest that SCF FBXW2 is an important mediator in the context of metabolic diseases. The development of FBXW2 (P3)-mimicking inhibitors and small-molecular drugs specifically abrogating KSRP ubiquitination-dependent inflammatory responses are viable approaches for obesity and atherosclerosis treatment.

AMP‐activated protein kinase α1 phosphorylates PHD2 to maintain systemic iron homeostasis

“…Western blots and immunohistochemical staining were performed as described. 28 , 29 , 30 Antibodies used were SLC40A1 (NBP1‐21502, Novus Biologicals, Centennial, CO, USA, 1:500), GAPDH (sc‐32233, Santa Cruz Biotechnology, Dallas, TX, USA, 1:2000), AMPKα1 (2795, Cell Signaling Technology, Danvers, MA, USA, 1:1000 and sc‐19128, Santa Cruz Biotechnology, 1:500), AMPK‐α2 (2757, Cell Signaling Technology, 1:1000 and sc‐19131, Santa Cruz Biotechnology, 1:1000), pAMPK (Thr172, 2535, Cell Signaling Technology, 1:1000), Smad1/5/8 (sc‐6031, Santa Cruz Biotechnology, 1:1000), pSmad1/5/8 (9511, Cell Signaling Technology, 1:1000), HIF1α (14179, Cell Signaling Technology, 1:1000), Hydroxy‐HIF1α (Pro564) (3434, Cell Signaling Technology, 1:1000), pSer/Thr (ab17464, Abcam, 1:1000 ), PHD2 (4835, Cell Signaling Technology, 1:1000), HA (3724, Cell Signaling Technology, 1:1000) and His (12698, Cell Signaling Technology, 1:1000).…”

Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

“…The cellular levels of RBPs, as master regulators of gene expression, are continuously adjusted via UPS. For instance, KSRP proteasome-mediated turnover controls the exosome recruitment activity of this ARE-RBP for target mRNA degradation ( García-Mayoral et al, 2007 ; Díaz-Moreno et al, 2010 ; Gherzi et al, 2010 ; Briata et al, 2013 ; Wang et al, 2020 ). As another example, HuR ubiquitylation specifically at Lys182 has been related to a decrease in its cellular levels after heat shock ( Abdelmohsen et al, 2009 ).…”

“…Ubiquitylation of KSRP has also been associated to metabolic disorders such as atherosclerosis and obesity. The pathological upregulation of the E3 Ub-ligase F-box/WD repeat-containing protein 2 (FBXW2) in macrophages increases KSRP degradation, undermining the normal translational repression of pro-inflammatory factors by this RBP ( Wang et al, 2020 ). On the other hand, ubiquitylated KSRP has also exhibited high activity against picornavirus infection.…”

Table_1.pdf

“…The cellular levels of RBPs, as master regulators of gene expression, are continuously adjusted via UPS. For instance, KSRP proteasome-mediated turnover controls the exosome recruitment activity of this ARE-RBP for target mRNA degradation (García-Mayoral et al, 2007;Díaz-Moreno et al, 2010;Gherzi et al, 2010;Briata et al, 2013;Wang et al, 2020). As another example, HuR ubiquitylation specifically at Lys182 has been related to a decrease in its cellular levels after heat shock (Abdelmohsen et al, 2009).…”

“…Ubiquitylation of KSRP has also been associated to metabolic disorders such as atherosclerosis and obesity. The pathological upregulation of the E3 Ub-ligase F-box/WD repeat-containing protein 2 (FBXW2) in macrophages increases KSRP degradation, undermining the normal translational repression of proinflammatory factors by this RBP (Wang et al, 2020). On the other hand, ubiquitylated KSRP has also exhibited high activity against picornavirus infection.…”