PI3K säätelyllinen alayksikkö silppuroituu BTB- Kelch perheen proteiinista KBTBD2

https://www.ncbi.nlm.nih.gov/gene/25948

Also known as

BKLHD1

Expression

Ubiquitous expression in gall bladder (RPKM 16.7), bone marrow (RPKM 14.7) and 25 other tissues See more

Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6418-E6426. Epub 2016 Oct 5.

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

Zhang Z¹, Turer E¹, Li X¹, Zhan X¹, Choi M¹, Tang M¹, Press A¹, Smith SR², Divoux A², Moresco EM¹, Beutler B³.

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 proteasome-mediated 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.

KEYWORDS:

Kbtbd2; diabetes; insulin resistance; p85α; ubiquitination