Cuproptosis:a new v form of programmed cell death

A recent study by Tsvetkov et al.was published in Science and proposed a novel form of copper-induced cell death.Tsvetkov et al.revealed that excess intracellular copper induces the aggregation of lipoylated dihydrolipoamide S-acetyltransferase(DLAT),which is associated with the mitochondrial tricarboxylic acid(TCA)cycle,resulting in proteotoxic stress and leading to a novel form of cell death termed cuproptosis[1].

VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type Ⅰ receptor degradation

The transforming growth factor-β(TGF-β)family controls embryogenesis,stem cell differentiation,and tissue homeostasis.However,how post-translation modifications contribute to fine-tuning of TGF-βfamily signaling responses is not well understood.Inhibitory(I)-Smads can antagonize TGF-β/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-βreceptor for proteasomal degradation.A proteomic interaction screen identified Vpr binding protein(VprBP)as novel binding partner of Smad7.Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation,Smad2–Smad4 interaction,as well as TGF-βtarget gene expression.VprBP was found to promote Smad7–Smurf1–TβRI complex formation and induce proteasomal degradation of TGF-βtype I receptor(TβRI).Moreover,VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination.In multiple adult and mouse embryonic stem cells,depletion of VprBP promotes TGF-βor Activin-induced responses.In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression,and VprBP attenuated mesoderm induction during zebrafish embryogenesis.Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-βand Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.

The DDB1-DCAF2 complex is essential for B cell development because it regulates cell cycle progression

B cell development in the bone marrow is critical for producing numerous B cells that play an essential role in the adaptive immune response.B cells develop from common lymphoid progenitors(CLPs),which then differentiate through a series of stages,which include prepro-B cells,pro-B cells,pre-B cells,immature B cells,and mature B cells.

TBK1:a new target for overcoming cancer immunotherapy resistance

In a recent study published in Nature,Sun et al.(2023)discovered that targeting TANK-binding kinase 1(TBK1)can successfully overcome resistance to immune checkpoint blockade(ICB)treatment and the study revealed its potential mechanism.The authors provided evidence that the disruption of TBK1 signal enhances the blockade of programmed cell death protein-1(PD-1)and promotes anti-tumor immunity in the tumor microenvironment(TME).Tumor cells rely on Janus kinase(JAK)and signal transducer as well as activator of transcription(STAT)signals to elicit an immune response by perceiving tumor necrosis factorα(TNF-α)and interferon-γ(IFN-γ),resulting in receptor-interacting protein kinase(RIPK)-caspase-mediated cell death in tumor cells(Figure 1).

Nucleolar GTPase Bms1 displaces Ttf1 from RFB-sites to balance progression of rDNA transcription and replication

18S,5.8S,and 28S ribosomal RNAs(rRNAs)are cotranscribed as a pre-ribosomal RNA(pre-rRNA)from the rDNA by RNA polymerase I whose activity is vigorous during the S-phase,leading to a conflict with rDNA replication.This conflict is resolved partly by replication-fork-barrier(RFB)-sites sequences located downstream of the rDNA and RFB-binding proteins such as Ttf1.However,how Ttf1 is displaced from RFB-sites to allow replication fork progression remains elusive.Here,we reported that loss-of-function of Bms1l,a nucleolar GTPase,upregulates rDNA transcription,causes replication-fork stall,and arrests cell cycle at the S-to-G2 transition;however,the G1-to-S transition is constitutively active characterized by persisting DNA synthesis.Concomitantly,ubf,tif-IA,and taf1b marking rDNA transcription,Chk2,Rad51,and p53 marking DNA-damage response,and Rpa2,PCNA,Fen1,and Ttf1 marking replication fork stall are all highly elevated in bms1l mutants.We found that Bms1 interacts with Ttf1 in addition to Rc1l.Finally,we identified RFB-sites for zebrafish Ttf1 through chromatin immunoprecipitation sequencing and showed that Bms1 disassociates the Ttf1–RFB complex with its GTPase activity.We propose that Bms1 functions to balance rDNA transcription and replication at the S-phase through interaction with Rcl1 and Ttf1,respectively.TTF1 and Bms1 together might impose an S-phase checkpoint at the rDNA loci.

WDR74 functions as a novel coactivator in TGF-β signaling

Smads are critical intracellular signal transducers for transforming growth factor-β(TGF-β) in mammalian cells. In this study, we have identified WD repeat-containing protein 74(WDR74) as a novel transcriptional coactivator for Smads in the canonical TGF-β signaling pathway. Through direct interactions with Smad proteins, WDR74 enhances TGF-β-mediated phosphorylation and nuclear accumulation of Smad2 and Smad3. Consequently, WDR74 enables stronger transcriptional responses and more robust TGF-β-induced physiological responses. Our findings have elucidated a critical role of WDR74 in regulating TGF-β signaling.

Fragmentation for selection: how the deleterious mt DNA is removed in the female germline

Mitochondria are the energy factories and metabolic centers of cells,and their malfunction can lead to multiple human diseases.As highly dynamic organelles,mitochondria undergo frequent fission and fusion processes[1].The fusion process enables the exchange of inner materials between individual mitochondrion.The materials from healthy mitochondria could potentially compensate for the defects found in the defective mitochondria.Fission processes not only increase the mitochondrial number but also separate the damaged parts of mitochondria from the healthy ones,thus,facilitating the elimination of the defective mitochondria through a process known as mitophagy.Excessive fusion leads to extra connections and branching of the mitochondria,whereas extra fission results in fragmentation of mitochondria.The fusion and fission processes are differently tuned in various tissues to adapt to different physiological requirements[2].

Cancer Environment Immunotherapy: targeting TGF-β finds its way towards tissue healing and vasculature remodeling

Recently,Prof.Ming 0.Li and colleagues published two back-toback studies in Nature,demonstrating that blocking transforming growth factor β(TGF-β)signaling in CD4^(+) T cells leads to tissue healing and remodeling of the blood vasculature,causing cancer cell hypoxia and death in distant avascular regions.1 Furthermore,they also provide direct evidence validating that the above strategy does restrain cancer progression in a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies.

An effective platform for cancer immunotherapy:pooled knockin targeting for genome engineering

Recently,a paper published in Cell by Theodore L.Roth et al.reported the development of a platform to assess the functional effects of pooled knockin constructs targeting a specific locus in the genome.It also provided a strategy that allows discovery of novel synthetic constructs in the pools to enable engineering T cells with gain of function and promote antitumor activity of T cells in vivo.

Recent advances in the neural regulation of feeding behavior in adult Drosophila

The ability to maintain metabolic homeostasis is a key capability critical for the survival and well-being of animals living in constantly changing environments.Metabolic homeostasis depends on neuromodulators,such as biogenic amines,neuropeptides,and hormones,to signal changes in animals’ internal metabolic status and to orchestrate their behaviors accordingly.An important example is the regulation of feeding behavior by conserved molecular and cellular mechanisms across the animal kingdom.Its relatively simple brain coupled with well-characterized genetics and behavioral paradigms makes the fruit fly Drosophila melanogaster an excellent model for investigating the neuromodulatory regulation of feeding behavior.In this review we discuss the neuromodulators and neural circuits that integrate the internal physiological status with external sensory cues and modulate feeding behavior in adult fruit flies.Studies show that various specific aspects of feeding behavior are subjected to unique neuromodulatory regulation,which permits fruit flies to maintain metabolic homeostasis effectively.

STING,a critical contributor to SARS-CoV-2 immunopathology

Recently,a study published in Nature by Domizio et al.1 revealed the underlying mechanism of aberrant immunopathology during the late phase of infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The authors provided evidence demonstrating that stimulator of interferon genes(STING)plays a unique role in the alveolus-capillary cytokine storm induced by mitochondrial DNA(mtDNA)during coronavirus disease 2019(COVID-19)(Fig.1).Some studies stressed that the STING agonists block the SARS-CoV-2 infection via triggering the type I interferons(IFNs)response,2,3 while others revealed that SARS-CoV-2 induces the chromatin DNA traveling to cytosol by promoting the cell-tocell fusion,resulting in the activation of cGAS-STING signaling.

Activated STING: an ion channel to trigger non-interferon-related functions

Recently,a study published in Science by Liu et al.1 presented compelling evidence demonstrating that upon translocation to the Golgi apparatus,STING(Stimulator of Interferon Genes)serves as a direct mediator for proton release into the cytosol,thereby instigating non-canonical LC3B(light-chain 3B)lipidation and NLRP3(NOD-like receptor family pyrin domain–containing 3)inflammasome activation(Fig.1).This study offers a new perspective on the involvement of the cGAS-STING pathway in non-interferon-related functions.

cGAS-like receptors: new RNA sensors in Drosophila

Recently,two back-to-back studies(Slavik et al.1 and Holleufer et al.2)were published in Nature,identifying that cGAS-like receptors(cGLRs)extensively exist in Drosophila and act as nucleic acid sensors in the antiviral immune system.Furthermore,they also provided evidence demonstrating that cGLRs in Drosophila can sense dsRNA and produce 3′2′-cGAMP(cG[3′–5′]pA[2′–5′]p)as a second messenger that activates the Sting-dependent antiviral immune response.

ADP-riboxanation:a new pyroptosis evasion strategy

A recent study published in Nature by Li et al.(2021)revealed the underlying mechanism by which Shigella flexneri evades host pyroptosis using a type III secretion system(T3SS)effector,OspC3.OspC3 suppresses the proteolytic activity of caspase-11 or caspase-4(hereafter referred to as‘caspase-11/4’)in a nicotinamide adenine dinucleotide(NAD+)-dependent manner by catalyzing adenosine diphosphate riboxanation(ADP-riboxanation)on arginine 314(Arg314)and Arg310 in caspase-4 and caspase-11,respectively(Figure 1).In addition,S.flexneriΔicsAΔospC3 is a live-attenuated vaccine candidate.

Novel pyroptosis-independent functions of gasdermins

Recently,Rana et al.and Zhang et al.published two studies illustrating the important regulatory roles of gasdermin B(GSDMB)and-D(GSDMD)in inflammatory bowel disease(IBD)and intestinal immune homeostasis maintenance,respectively.1,2 Their findings collectively indicate that the gasdermins(GSDMs)can play a crucial role in restoring epithelial barrier function and shaping gut mucosal homeostasis.Moreover,neither of the functions of GSDMs revealed by these two studies are related to pyroptosis,which may provide new insights into the non-pyroptosis-dependent functions of GSDM proteins.