The peroxisome proliferator-activated receptor γ (PPARγ) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPARγ. Both endogenous and exogenous PPARγ associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPARγ through its deubiquitinating activity. Site-directed mutagenesis experiments showed that the Lys⁴⁶² residue of PPARγ is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPARγ stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPARγ protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARγ in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARγ target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARγ and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPARγ are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs.

Exon splicing triggered by unpredicted genetic mutation can cause translational variations in neurodegenerative disorders. In this study, we discovered Alzheimer’s disease (AD)-specific single-nucleotide variants (SNVs) and abnormal exon splicing of the phospholipase c gamma-1 ( PLCγ1 ) gene using genome-wide association study (GWAS) and a deep learning-based exon splicing prediction tool. GWAS revealed that the identified single-nucleotide variations were mainly distributed in the H3K27ac-enriched region of the PLCγ1 gene body during brain development in an AD mouse model. A deep learning analysis, trained with human genome sequences, predicted 14 splicing sites in the human PLCγ1 gene, one of which completely matched an SNV in exon 27 of the PLCγ1 gene in an AD mouse model. In particular, the SNV in exon 27 of the PLCγ1 gene is associated with abnormal splicing during messenger RNA maturation. Taken together, our findings suggest that this approach, which combines in silico and deep learning-based analyses, has potential for identifying the clinical utility of critical SNVs in AD prediction.

Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3γ

Autophagy is a critical cellular mechanism that regulates the degradation of misfolded and aggregated proteins and non-functional intracellular organelles. Based on the fundamental qualities of the substrates targeted for degradation and the distinct molecular mechanisms involved, autophagy can be classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy—including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62—in cancer progression.

The prevalence of Alzheimer's disease (AD) and its associated economic and societal burdens are on the rise, but there are no curative treatments for AD. Interestingly, this neurodegenerative disease shares several biological and pathophysiological features with cancer, including cell-cycle dysregulation, angiogenesis, mitochondrial dysfunction, protein misfolding, and DNA damage. However, the genetic factors contributing to the overlap in biological processes between cancer and AD have not been actively studied. In this review, we discuss the shared biological features of cancer and AD, the molecular targets of anticancer drugs, and therapeutic approaches. First, we outline the common biological features of cancer and AD. Second, we describe several anticancer drugs, their molecular targets, and their effects on AD pathology. Finally, we discuss how protein-protein interactions (PPIs), receptor inhibition, immunotherapy, and gene therapy can be exploited for the cure and management of both cancer and AD. Collectively, this review provides insights for the development of AD theragnostics based on cancer drugs and molecular targets.