Yu Zhang

Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.

Methyl‐CpG binding protein 2 (MeCP2) is an important X‐linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss‐of‐function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia–reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48‐linked ubiquitination from MeCP2 prevented its proteasome‐dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin‐specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia‐induced MeCP2 degradation by cleaving lysine 48‐linked ubiquitin chains from MeCP2, primarily targeting its C‐terminal domain. Consistently, USP15 inhibited hypoxia‐induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL‐6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL‐6 signaling.

The redox-active metal ions, especially Cu²⁺, are highly correlated to Alzheimer's disease (AD) by causing metal ion-mediated oxidative stress and toxic metal-bound β-amyloid (Aβ) aggregates. Numerous pieces of evidence have revealed that the regulation of metal homeostasis could be an effective therapeutic strategy for AD. Herein, in virtue of the interaction of both amino-containing silane and ethylenediaminetetraacetic acid disodium salt for Cu²⁺, the silicon-carbon dots (SiCDs) are deliberately prepared using these two raw materials as the cocarbon source; meanwhile, to realize the local enrichment of SiCDs and further maximize the chelating ability to Cu²⁺, the SiCDs are feasibly loaded to the biocompatible mesoporous silica nanoparticles (mSiO₂) with the interaction between residual silane groups on SiCDs and silanol groups of mSiO₂. Thus-obtained nanocomposites (i.e., mSiO₂@SiCDs) could serve as an efficient Cu²⁺ chelator with satisfactory metal selectivity and further modulate the enzymic activity of free Cu²⁺ and the Aβ₄₂-Cu²⁺ complex to alleviate the pathological oxidative stress with an anti-inflammatory effect. Besides, mSiO₂@SiCDs show an inspiring inhibitory effect on Cu²⁺-mediated Aβ aggregation and further protect the neural cells against the toxic Aβ₄₂-Cu²⁺ complex. Moreover, the transgenic Caenorhabditis elegans CL2120 assay demonstrates the protective efficacy of mSiO₂@SiCDs on Cu²⁺-mediated Aβ toxicity in vivo, indicating its potential for AD treatment.

Nonsmall cell lung cancer (NSCLC) is highly malignant with limited treatment options, platinum-based chemotherapy is a standard treatment for NSCLC with resistance commonly seen. NSCLC cells exploit enhanced antioxidant defense system to counteract excessive reactive oxygen species (ROS), which contributes largely to tumor progression and resistance to chemotherapy, yet the mechanisms are not fully understood. Recent studies have suggested the involvement of histones in tumor progression and cellular antioxidant response; however, whether a major histone variant H1.2 (H1C) plays roles in the development of NSCLC remains unclear. Herein, we demonstrated that H1.2 was increasingly expressed in NSCLC tumors, and its expression was correlated with worse survival. When crossing the H1c knockout allele with a mouse NSCLC model ( Kras ^LSL-G12D/+ ), H1.2 deletion suppressed NSCLC progression and enhanced oxidative stress and significantly decreased the levels of key antioxidant glutathione (GSH) and GCLC, the catalytic subunit of rate-limiting enzyme for GSH synthesis. Moreover, high H1.2 was correlated with the IC50 of multiple chemotherapeutic drugs and with worse prognosis in NSCLC patients receiving chemotherapy; H1.2-deficient NSCLC cells presented reduced survival and increased ROS levels upon cisplatin treatment, while ROS scavenger eliminated the survival inhibition. Mechanistically, H1.2 interacted with NRF2, a master regulator of antioxidative response; H1.2 enhanced the nuclear level and stability of NRF2 and, thus, promoted NRF2 binding to GCLC promoter and the consequent transcription; while NRF2 also transcriptionally up-regulated H1.2. Collectively, these results uncovered a tumor-driving role of H1.2 in NSCLC and indicate an “H1.2-NRF2” antioxidant feedforward cycle that promotes tumor progression and chemoresistance.

During viral infection, sensing of viral RNA by retinoic acid–inducible gene-I–like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O -linked β-d- N -acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus–triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.

Angiopoietin‐like proteins (ANGPTLs), a family of eight secreted glycoproteins termed ANGTPL1‐8, are involved in angiogenesis, lipid metabolism, cancer progression, and inflammation. Their roles in regulating lipid metabolism have been intensively studied, as some ANGPTLs are promising pharmacological targets for hypertriglyceridemia and associated cardiovascular disease. Recently, the emerging roles of ANGPTLs in inflammation have attracted great attention. First, elevated levels of multiple circulating ANGPTLs in inflammatory diseases make them potential disease biomarkers. Second, multiple ANGPTLs regulate acute or chronic inflammation via various mechanisms, including triggering inflammatory signaling through their action as ligands for integrin or forming homo‐ /hetero‐oligomers to regulate signal transduction via extra‐ or intracellular mechanisms. As dysregulation of the inflammatory response is a critical trigger in many diseases, understanding the roles of ANGPTLs in inflammation will aid in drug/therapy development. Here, we summarize the roles, mechanisms, and potential therapeutic values for ANGPTLs in inflammation and inflammatory diseases.

COVID-19 patients present high incidence of kidney abnormalities, which are associated with poor prognosis and high mortality. Identification of SARS-CoV-2 in kidney of COVID-19 patients suggests renal tropism and direct infection. Presently, it is generally recognized that SARS-CoV-2 initiates invasion through binding of receptor-binding domain (RBD) of spike protein to host cell-membrane receptor ACE2, however, whether there is additional target of SARS-CoV-2 in kidney remains unclear. Kidney injury molecule-1 (KIM1) is a transmembrane protein that drastically up-regulated after renal injury. Here, binding between SARS-CoV2-RBD and the extracellular Ig V domain of KIM1 was identified by molecular simulations and co-immunoprecipitation, which was comparable in affinity to that of ACE2 to SARS-CoV-2. Moreover, KIM1 facilitated cell entry of SARS-CoV2-RBD, which was potently blockaded by a rationally designed KIM1-derived polypeptide. Together, the findings suggest KIM1 may mediate and exacerbate SARS-CoV-2 infection in a ‘vicious cycle’, and KIM1 could be further explored as a therapeutic target.

Tumor necrosis factor α (TNFα)‐ and interleukin 1β (IL‐1β)‐induced nuclear factor‐κB (NF‐κB) activation play key roles in inflammation, immunity, and cancer development. Here, we identified one of the deubiquitinating enzymes (DUBs), ubiquitin‐specific protease 15 (USP15), as a positive regulator in both TNFα‐ and IL‐1β‐induced NF‐κB activation. Overexpression of USP15 potentiated TNFα‐ or IL‐1β‐triggered NF‐κB activation and downstream gene transcription, whereas knockdown of USP15 had opposite effects. Mechanistically, upon TNFα stimulation, USP15 showed an enhanced interaction with transforming growth factor‐β activated kinase‐1 (TAK1)‐TAK1 binding protein (TAB) complex to inhibit the proteolysis of TAB2/3 by different pathways. Apart from deubiquitination dependently inducing cleavage of lysine 48‐linked TAB2 ubiquitination, USP15 also DUB independently inhibited lysosome‐associated TAB2 degradation, thus enhanced TAB2 stabilization. For TAB3, USP15 inhibited NBR1‐mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity. Together, our results reveal a novel USP15‐mediated mechanism through which efficient NF‐κB activation is achieved by differentially maintaining the TAB2/3 stability.