Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

A glimpse at the metabolic research in China.

Over the last few decades, China has witnessed a great leap in economic growth and social welfare. Unfortunately, Chinese people have also been affected by a pandemic of over-nutrition, lack of physical activity, and increasing prevalence of metabolic disorders including obesity, diabetes, non-alcohol fatty liver disease, and cardiovascular disease. For instance, China currently has the largest number of diabetic patients (∼116 million) in the world. The fire of metabolic disorders is further fanned by the increased aging population, according to the survey results from the National Bureau of Statistics. On the other hand, progress in metabolic research has also made big strides. Here, we offer a glimpse at metabolic research in China, including not only its status quo but also its prospects, which aims to make significant contributions to our understanding of metabolism from bench to bedside.

Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription.

Recent studies on enzymes and reader proteins for histone crotonylation support a function of histone crotonylation in transcription. However, the enzyme(s) responsible for histone decrotonylation (HDCR) remains poorly defined. Moreover, it remains to be determined if histone crotonylation is physiologically significant and functionally distinct from or redundant to histone acetylation. Here we present evidence that class I histone deacetylases (HDACs) rather than sirtuin family deacetylases (SIRTs) are the major histone decrotonylases, and that histone crotonylation is as dynamic as histone acetylation in mammalian cells. Notably, we have generated novel HDAC1 and HDAC3 mutants with impaired HDAC but intact HDCR activity. Using these mutants we demonstrate that selective HDCR in mammalian cells correlates with a broad transcriptional repression and diminished promoter association of crotonylation but not acetylation reader proteins. Furthermore, we show that histone crotonylation is enriched in and required for self-renewal of mouse embryonic stem cells.

Regulation of Ubiquitin-like with Plant Homeodomain and RING Finger Domain 1 (UHRF1) Protein Stability by Heat Shock Protein 90 Chaperone Machinery.

As a protein critical for DNA maintenance methylation and cell proliferation, UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy. In a high throughput screening for small molecules that induce UHRF1 protein degradation, we have identified the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). We present evidence that UHRF1 interacts with HSP90 chaperone complex and is a novel HSP90 client protein. Pharmacological inhibition of HSP90 with 17-AAG or 17-dimethylaminoethylamino-17-demethoxygeldanamycin results in UHRF1 ubiquitination and proteasome-dependent degradation. Interestingly, this HSP90 inhibitor-induced UHRF1 degradation is independent of CHIP and CUL5, two previously identified ubiquitin E3 ligases for HSP90 client proteins. In addition, this degradation is dependent neither on the intrinsic E3 ligase of UHRF1 nor on the E3 ligase SCF(ß-TRCP) that has been implicated in regulation of UHRF1 stability. We also provide evidence that HSP90 inhibitors may suppress cancer cell proliferation in part through its induced UHRF1 degradation. Taken together, our results identify UHRF1 as a novel HSP90 client protein and shed light on the regulation of UHRF1 stability and function.