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Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8 + T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy. The regulatory mechanisms of PD-L1 posttranslational modifications are not completely understood. Here the authors show that USP8 negatively regulates PD-L1 protein abundance by removing the K63-linked ubiquitination of PD-L1; while USP8 inhibition increases MHC-I expression and triggers anti-tumour immune responses through activating NF-κB signalling.

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy. Ubiquitination and deubiquitination processes regulate the stability of PD-1, affecting T cell biology. Here the authors identify the ubiquitin-specific protease 5 (USP5) as a deubiquitinase for PD-1 and show that USP5 inhibition in combination with a MEK inhibitor or anti-CTLA-4 could promote anti-tumor immune responses in preclinical models.

Background Centromeres are critical for maintaining genomic stability in eukaryotes, and their turnover shapes genome architectures and drives karyotype evolution. However, the co-evolution of centromeres from different species in allopolyploids over millions of years remains largely unknown. Results Here, we generate three near-complete genome assemblies, a tetraploid Brachypodium hybridum and its two diploid ancestors, Brachypodium distachyon and Brachypodium stacei . We detect high degrees of sequence, structural, and epigenetic variations of centromeres at base-pair resolution between closely related Brachypodium genomes, indicating the appearance and accumulation of species-specific centromere repeats from a common origin during evolution. We also find that centromere homogenization is accompanied by local satellite repeats bursting and retrotransposon purging, and the frequency of retrotransposon invasions drives the degree of interspecies centromere diversification. We further investigate the dynamics of centromeres during alloploidization process, and find that dramatic genetics and epigenetics architecture variations are associated with the turnover of centromeres between homologous chromosomal pairs from diploid to tetraploid. Additionally, our pangenomes analysis reveals the ongoing variations of satellite repeats and stable evolutionary homeostasis within centromeres among individuals of each Brachypodium genome with different polyploidy levels. Conclusions Our results provide unprecedented information on the genomic, epigenomic, and functional diversity of highly repetitive DNA between closely related species and their allopolyploid genomes at both coarse and fine scale.

The Knl1-Mis12-Ndc80 (KMN) network is an essential component of the kinetochore–microtubule attachment interface, which is required for genomic stability in eukaryotes. However, little is known about plant Knl1 proteins because of their complex evolutionary history. Here, we cloned the Knl1 homolog from maize (Zea mays) and confirmed it as a constitutive central kinetochore component. Functional assays demonstrated their conserved role in chromosomal congression and segregation during nuclear division, thus causing defective cell division during kernel development when Knl1 transcript was depleted. A 145 aa region in the middle of maize Knl1, that did not involve the MELT repeats, was associated with the interaction of spindle assembly checkpoint (SAC) components Bub1/Mad3 family proteins 1 and 2 (Bmf1/2) but not with the Bmf3 protein. They may form a helical conformation with a hydrophobic interface with the TPR domain of Bmf1/2, which is similar to that of vertebrates. However, this region detected in monocots shows extensive divergence in eudicots, suggesting that distinct modes of the SAC to kinetochore connection are present within plant lineages. These findings elucidate the conserved role of the KMN network in cell division and a striking dynamic of evolutionary patterns in the SAC signaling and kinetochore network.

The CD47/SIRPα axis conveys a ‘don’t eat me’ signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8 + T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity. Clinical trials of CD47 blocking antibody in human cancer patients have not yielded ideal results. Here the authors show that USP2 stabilizes CD47 through deubiquitination, whereas USP2 inhibition enhances macrophage phagocytosis, reprograms tumor microenvironment and synergizes with anti-PD-1 treatment.

This paper focuses on event-triggered state estimation and control of positive complex networks. An event-triggered condition is provided for discrete-time complex networks by which an event-based state estimator and an estimator-based controller are designed through matrix decomposition technology. Thus, the system is converted to an interval uncertain system. The positivity and the L1-gain stability of complex networks are ensured by resorting to a co-positive Lyapunov function. All conditions are solvable in terms of linear programming. Finally, the effectiveness of the proposed state estimator and controller are verified by a numerical example. The main contributions of this paper are as follows: (i) A positive complex network framework is constructed based on an event-triggered strategy, (ii) a new state estimator and an estimator-based controller are proposed, and (iii) a simple analysis and design approach consisting of a co-positive Lyapunov function and linear programming is presented for positive complex networks.

T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA N 6 2′- O -dimethyladenosine (m 6 A m ) methyltransferase, negatively regulates CD8 + T cell antitumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) reduced tumor growth in mice. Single-cell RNA sequencing shows an increase in the number of tumor-infiltrating cytotoxic CD8 + T cells in Pcif1 -deficient mice. Mechanistically, proteomic and m 6 A m -sequencing analyses pinpoint that Pcif1 KO elevates m 6 A m -modified targets, specifically ferroptosis suppressor genes ( Fth1 , Slc3a2 ), and the T cell activation gene Cd69 , imparting resistance to ferroptosis and enhancing CD8 + T cell activation. Of note, Pcif1 -deficient mice had enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO chimeric antigen receptor T cells improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells have enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8 + T cell activation and targeting PCIF1 is a promising strategy to boost antitumor immunity. Here the authors show that PCIF1 can regulate CD8 + T cell antitumor responses in mice and use this information to enhance chimeric antigen receptor T cell design.

Polyploidization is a process which is related to species hybridization and whole genome duplication. It is widespread among angiosperm evolution and is essential for speciation and diversification. Allopolyploidization is mainly derived from interspecific hybridization and is believed to pose chromosome imbalances and genome instability caused by meiotic irregularity. However, the self-compatible allopolyploid in wild nature is cytogenetically and genetically stable. Whether this stabilization form was achieved in initial generation or a consequence of long term of evolution was largely unknown. Here, we synthesized a series of nascent allotetraploid wheat derived from three diploid genomes of A, S*, and D. The chromosome numbers of the majority of the progeny derived from these newly formed allotetraploid wheat plants were found to be relatively consistent, with each genome containing 14 chromosomes. In meiosis, bivalent was the majority of the chromosome configuration in metaphase I which supports the stable chromosome number inheritance in the nascent allotetraploid. These findings suggest that diploidization occurred in the newly formed synthetic allotetraploid wheat. However, we still detected aneuploids in a proportion of newly formed allotetraploid wheat, and meiosis of these materials present more irregular chromosome behavior than the euploid. We found that centromere pairing and centromere clustering in meiosis was affected in the aneuploids, which suggest that aneuploidy may trigger the irregular interactions of centromere in early meiosis which may take participate in promoting meiosis stabilization in newly formed allotetraploid wheat.

The lack of resistance resources is a major bottleneck for wheat Fusarium head blight (FHB) resistance breeding. Three wheat-Th. elongatum FHB resistant translocation lines have been developed and used for wheat breeding without yield penalty. Transcriptomic analysis identified a derivative glutathione S-transferase transcript T26102, which was homologous to Fhb7 and induced dramatically by Fusarium graminearum. Unlike other studies, Fhb7 homologs were detected not only in Thinopyrum but also in Elymus, Leymus, Pseudoroegeria and Roegeria. We also found that several wheat-Th. ponticum derivatives carrying Fhb7 and its homologs were highly susceptible to FHB. Moreover, the transgenic plants expressing Fhb7 and its homolog on different backgrounds did not improve the FHB resistance. Competing Interest Statement The authors have declared no competing interest.