Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

We have identified and characterized a Microtubule Interacting and Transport (MIT) domain at the N terminus of the deubiquitinating enzyme UBPY/USP8. In common with other MIT-containing proteins such as AMSH and VPS4, UBPY can interact with CHMP proteins, which are known to regulate endosomal sorting of ubiquitinated receptors. Comparison of binding preferences for the 11 members of the human CHMP family between the UBPY MIT domain and another ubiquitin isopeptidase, AMSH, reveals common interactions with CHMP1A and CHMP1B but a distinct selectivity of AMSH for CHMP3/VPS24, a core subunit of the ESCRT-III complex, and UBPY for CHMP7. We also show that in common with AMSH, UBPY deubiquitinating enzyme activity can be stimulated by STAM but is unresponsive to its cognate CHMPs. The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. This is functionally significant as an MIT-deleted UBPY mutant is unable to rescue its binding partner STAM from proteasomal degradation or reverse a block to epidermal growth factor receptor degradation imposed by small interfering RNA-mediated depletion of UBPY.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

The PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. The present study investigated the effects of the flavonoid apigenin on the PD-L1 expression and the tumorigenesis of melanoma. The influence of flavonoids on melanoma cell growth and apoptosis was investigated using cell proliferation and flow cytometric analyses. The differential IFN-γ-induced PD-L1 expression and STAT1 activation were examined in curcumin and apigenin-treated melanoma cells using immunoblotting or immunofluorescence assays. The effects of flavonoid treatment on melanoma sensitivity towards T cells were investigated using Jurkat cell killing, cytotoxicity, cell viability, and IL-2 secretion assays. Melanoma xenograft mouse model was used to assess the impact of flavonoids on tumorigenesis in vivo. Human peripheral blood mononuclear cells were used to examine the influence of flavonoids on PD-L1 expression in dendritic cells and cytotoxicity of cocultured cytokine-induced killer cells by cell killing assays. Curcumin and apigenin showed growth-suppressive and pro-apoptotic effects on melanoma cells. The IFN-γ-induced PD-L1 upregulation was significantly inhibited by flavonoids, especially apigenin, with correlated reductions in STAT1 phosphorylation. Apigenin-treated A375 cells exhibited increased sensitivity towards T cell-mediated killing. Apigenin also strongly inhibited A375 melanoma xenograft growth in vivo, with enhanced T cell infiltration into tumor tissues. PD-L1 expression in dendritic cells was reduced by apigenin, which potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells. Apigenin restricted melanoma growth through multiple mechanisms, among which its suppression of PD-L1 expression exerted a dual effect via regulating both tumor and antigen presenting cells. Our findings provide novel insights into the anticancer effects of apigenin and might have potential clinical implications.