Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice

Abstract

We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasomemediated degradation. In the absence of KBTBD2, p85α accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85α blocked the binding of p85α-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85α-encoding gene Pik3r1 rescued diabetes and hepatic steatosis phenotypes of Kbtbd2 −/− mice. Kbtbd2 was down-regulated in diet-induced obese insulin-resistant mice in a leptin-dependent manner. KBTBD2 is an essential regulator of the insulin-signaling pathway, modulating insulin sensitivity by limiting p85α abundance.diabetes | insulin resistance | Kbtbd2 | p85α | ubiquitination

5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

“…Interaction between PIK3R1 and other proteins could also modulate the ubiquitin‐mediated degradation of PIK3R1. Zhang et al reported that PIK3R1 ubiquitination is regulated by the binding between KBTDB2 and PIK3R1 . In the present study, we revealed that 5‐HT1D could interact with and stabilize PIK3R1 through suppressing its ubiquitin‐mediated degradation.…”

“…Then we wondered how 5‐HT1D affected the expression level of PIK3R1 in HCC. PIK3R1 ubiquitination and the subsequent proteasome‐mediated degradation has been indicated during metabolic disorder . We then speculated that 5‐HT1D might modulate the ubiquitin‐mediated degradation of PIK3R1 to affect PIK3R1 expression level.…”

“…In the present study, we revealed that 5‐HT1D could interact with and stabilize PIK3R1 through suppressing its ubiquitin‐mediated degradation. The protective role of 5‐HT1D in PIK3R1 degradation might also involve a third protein, potentially an E3 ubiquitin ligase, which will be investigated further in our future studies.…”

Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors

“…Interestingly, p110δ preferentially complexes with p85α compared with p85β. These results suggest that PI3Kδ is hard-wired to use p85α- or avoid p85β-specific properties or functions; e.g., phosphorylation ( 15 ) or p85β-directed ( 18 ) or 85α-directed ( 23 ) ubiquitination and degradation. It is noteworthy that the phenotypes of mice lacking p85α or expressing kinase-dead p110δ are most similar in B lymphocytes where PI3Kδ is dominant ( 31 , 32 ).…”

“…The concepts of p110-free and p110-independent functions of p85s have been raised many times, including a recent report that PIK3R1 (encoding p85α) can be a tumor suppressor ( 17 – 22 ) and evidence that p110-free p85s are targeted for isoform-specific degradation ( 18 , 23 ). Some work has provided evidence for specific p110-free regulatory subunit complexes ( 19 ); however, the best quantitative analysis of class IA PI3K subunit stoichiometry concluded there were no p110-free regulatory subunits ( 24 ).…”