NF‐κB is a pleiotropic transcription factor involved in multiple processes, including inflammation and oncogenesis. We have previously reported that COMMD1 represses κB‐dependent transcription by negatively regulating NF‐κB–chromatin interactions. Recently, ubiquitination of NF‐κB subunits has been similarly implicated in the control of NF‐κB recruitment to chromatin. We report here that COMMD1 accelerates the ubiquitination and degradation of NF‐κB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECSSOCS1). COMMD1‐deficient cells demonstrate stabilization of RelA, greater nuclear accumulation of RelA after TNF stimulation, de‐repression of several κB‐responsive genes, and enhanced NF‐κB‐mediated cellular responses. COMMD1 binds to Cul2 in a stimulus‐dependent manner and serves to facilitate substrate binding to the ligase by stabilizing the interaction between SOCS1 and RelA. Our data uncover that ubiquitination and degradation of NF‐κB subunits by this COMMD1‐containing ubiquitin ligase is a novel and critical mechanism of regulation of NF‐κB‐mediated transcription.

Nanoscale room-temperature ferroelectricity is ideal for developing advanced non-volatile high-density memories. However, reaching the thin film limit in conventional ferroelectrics is a long-standing challenge due to the presence of the critical thickness effect. van der Waals materials, thanks to their stable layered structure, saturated interfacial bonding and weak interlayer couplings, are promising for exploring ultra-thin two-dimensional (2D) ferroelectrics and device applications. Here, we demonstrate a switchable room-temperature ferroelectric diode built upon a 2D ferroelectric α-In2Se3 layer as thin as 5 nm in the form of a graphene/α-In2Se3 heterojunction. The intrinsic out-of-plane ferroelectricity of the α-In2Se3 thin layers is evidenced by the observation of reversible spontaneous electric polarization with a relatively low coercive electric field of ∼2 × 105 V cm-1 and a typical ferroelectric domain size of around tens μm2. Owing to the out-of-plane ferroelectricity of the α-In2Se3 layer, the Schottky barrier at the graphene/α-In2Se3 interface can be effectively tuned by switching the electric polarization with an applied voltage, leading to a pronounced switchable double diode effect with an on/off ratio of ∼105. Our results offer a new way for developing novel nanoelectronic devices based on 2D ferroelectrics.

The gene encoding COMM domain-containing 1 (COMMD1) is a prototypical member of the COMMD gene family that has been shown to inhibit both NF-κB-and HIF-mediated gene expression. NF-κB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion. In this study, we demonstrate that COMMD1 expression is frequently suppressed in human cancer and that decreased COMMD1 expression correlates with a more invasive tumor phenotype. We found that direct repression of COMMD1 in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 expression in mouse melanoma cells led to decreased lung metastasis in a mouse model. Decreased COMMD1 expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. Mechanistically, our studies show that COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1α, preventing its dimerization with HIF-1β and subsequent DNA binding and transcriptional activation. Altogether, our findings demonstrate a role for COMMD1 in tumor invasion and provide a detailed mechanism of how this factor regulates the HIF pathway in cancer cells.

NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.

The photocurrent generation in photovoltaics relies essentially on the interface of p-n junction or Schottky barrier with the photoelectric efficiency constrained by the Shockley-Queisser limit. The recent progress has shown a promising route to surpass this limit via the bulk photovoltaic effect for crystals without inversion symmetry. Here we report the bulk photovoltaic effect in two-dimensional ferroelectric CuInP2S6 with enhanced photocurrent density by two orders of magnitude higher than conventional bulk ferroelectric perovskite oxides. The bulk photovoltaic effect is inherently associated to the room-temperature polar ordering in two-dimensional CuInP2S6. We also demonstrate a crossover from two-dimensional to three-dimensional bulk photovoltaic effect with the observation of a dramatic decrease in photocurrent density when the thickness of the two-dimensional material exceeds the free path length at around 40 nm. This work spotlights the potential application of ultrathin two-dimensional ferroelectric materials for the third-generation photovoltaic cells.

NF-κB is the master regulator of the immune response and is responsible for the transcription of hundreds of genes controlling inflammation and immunity. Activation of NF-κB occurs in the cytoplasm through the kinase activity of the IκB kinase complex, which leads to translocation of NF-κB to the nucleus. Once in the nucleus, NF-κB transcriptional activity is regulated by DNA binding-dependent ubiquitin-mediated proteasomal degradation. We have identified the deubiquitinase Ubiquitin Specific Protease-7 (USP7) as a regulator of NF-κB transcriptional activity. USP7 deubiquitination of NF-κB leads to increased transcription. Loss of USP7 activity results in increased ubiquitination of NF-κB, leading to reduced promoter occupancy and reduced expression of target genes in response to Toll-like-and TNF-receptor activation. These findings reveal a unique mechanism controlling NF-κB activity and demonstrate that the deubiquitination of NF-κB by USP7 is critical for target gene transcription.

The transcription factor NF-kB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-kB subunits plays an important role in the termination of NF-kB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses kB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IkB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.[Keywords: NF-kB; RelA; GCN5; COMMD1; ubiquitin; Cul2] Supplemental material is available at http://www.genesdev.org.

High-density memory is integral in solid-state electronics. 2D ferroelectrics offer a new platform for developing ultrathin electronic devices with nonvolatile functionality. Recent experiments on layered α-In 2 Se 3 confirm its roomtemperature out-of-plane ferroelectricity under ambient conditions. Here, a nonvolatile memory effect in a hybrid 2D ferroelectric field-effect transistor (FeFET) made of ultrathin α-In 2 Se 3 and graphene is demonstrated. The resistance of the graphene channel in the FeFET is effectively controllable and retentive due to the electrostatic doping, which stems from the electric polarization of the ferroelectric α-In 2 Se 3 . The electronic logic bit can be represented and stored with different orientations of electric dipoles in the top-gate ferroelectric. The 2D FeFET can be randomly rewritten over more than 10 5 cycles without losing the nonvolatility. The approach demonstrates a prototype of rewritable nonvolatile memory with ferroelectricity in van der Waals 2D materials.