TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation.

Sumoylation regulates many cellular processes, but its role in signaling via the T cell antigen receptor (TCR) remains unknown. We found that the kinase PKC-θ was sumoylated upon costimulation with antigen or via the TCR plus the coreceptor CD28, with Lys325 and Lys506 being the main sumoylation sites. We identified the SUMO E3 ligase PIASxß as a ligase for PKC-θ. Analysis of primary mouse and human T cells revealed that sumoylation of PKC-θ was essential for T cell activation. Desumoylation did not affect the catalytic activity of PKC-θ but inhibited the association of CD28 with PKC-θ and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-θ and CD28. Our findings demonstrate that sumoylation controls TCR-proximal signaling and that sumoylation of PKC-θ is essential for the formation of a mature immunological synapse and T cell activation.

Spontaneous exciton dissociation in organic photocatalyst under ambient conditions for highly efficient synthesis of hydrogen peroxide.

SignificanceHydrogen peroxide is a highly competitive ready-to-use product for solar energy transformation. Nevertheless, the contemporary photosynthetic systems are not efficient enough, due to severe charge recombination caused by high activation energy and binding energy of the exciton. Herein, we achieve spontaneous exciton dissociation at room temperature. Moreover, the photosynthesis of H2O2 reaches between 9,366 and 12,324 µmol·g-1 from 9 AM to 4 PM in ambient conditions, that is, sunlight irradiation, real water including fresh water and seawater, room temperature, and open air. The ultrahigh photocatalytic efficiency in ambient conditions allows the solar-to-chemical conversion in a real cost-effective and sustainable way, which represents an important step toward real applications.

Ultraphotostable Phosphorescent Nanosensors for Sensing the Lysosomal pH at the Single-Cell Level over Long Durations.

Ultraphotostable phosphorescent nanosensors have been designed for continuously sensing the lysosome pH over a long duration. The nanosensors exhibited excellent photostability, high accuracy, and capability to measure pH values during cell proliferation for up to 7 days. By arranging a metal-ligand complex of long phosphorescence lifetime and pH indicator in silica nanoparticles, we discover efficient Förster resonance energy transfer, which converts the pH-responsive UV-vis absorption signal of the pH indicator into a phosphorescent signal. Both the phosphorescent intensity and lifetime change at different pH values, and intracellular pH values can be accurately measured by our custom-built rapid phosphorescent lifetime imaging microscopy. The excellent photostability, high accuracy, and good biocompatibility prove that these nanosensors are a useful tool for tracing the fluctuation of pH values during endocytosis. The methodology can be easily adapted to design new nanosensors with different pKa or for different kinds of intracellular ions, as there are hundreds of pH and ion indicators readily available.

Band Structure Optimized by Electron-Acceptor Cations for Sensitive Perovskite Single Crystal Self-Powered Photodetectors.

Low-dimensional perovskites afford improved stability against moisture, heat, and ionic migration. However, the low dimensionality typically results in a wide bandgap and strong electron-phonon coupling, which is undesirable for optoelectronic applications. Herein, semiconducting A-site organic cation engineering by electron-acceptor bipyridine (bpy) cations (2,2'-bpy2+ and 4,4'-bpy2+) is employed to optimize band structure in low-dimensional perovskites. Benefiting from the merits of lower lowest unoccupied molecular orbital (LUMO) energy for 4,4'-bpy2+ cation, the corresponding (4,4'-bpy)PbI4 is endowed with a smaller bandgap (1.44 eV) than the (CH3NH3)PbI3 (1.57 eV) benchmark. Encouragingly, an intramolecular type II band alignment formation between inorganic Pb-I octahedron anions and bpy2+ cations favors photogenerated electron-hole pairs separation. In addition, a shortening distance between inorganic Pb-I octahedral chains in (4,4'-bpy)PbI4 single crystal (SC) can effectively promote carrier transfer. As a result, a self-powered photodetector based on (4,4'-bpy)PbI4 SC exhibits 131 folds higher on/off ratio (3807) than the counterpart of (2,2'-bpy)2Pb3I10 SC (29). The presented result provides an effective strategy for exporting novel organic cation-based low-dimensional perovskite SC for high-performance optoelectronic devices.

Chiral Bis-phosphate Macrocycles for Catalytic, Efficient, and Enantioselective Electrophilic Fluorination.

Incorporation of privileged catalytic scaffolds into a macrocyclic skeleton represents an attractive strategy to furnish supramolecular catalysis systems with enzyme-mimetic cavity and multi-site cooperation. Herein we reported the synthesis, structure, binding properties and catalytic application of a series of chiral bis-phosphate macrocycles toward the challenging asymmetric electrophilic fluorination. With a large, integrated chiral cavity and two cooperative phosphate sites, these macrocycles exhibited good inclusion toward 1,4-diazabicyclo[2.2.2]octane (DABCO) dicationic ammoniums through complementary ion-pair and C-H⋅⋅⋅O interactions, as confirmed by crystallographic and solution binding studies. In fluorocyclization of tryptamines with Selectfluor reagent which has a similar DABCO-based dicationic structure, only 2 mol% macrocycle catalyst afforded the desired pyrroloindoline products in moderate yields and up to 91 % ee. For comparison, the acyclic mono-phosphate analogue gave obviously lower reactivity and enantioselectivity (<20 % ee), suggesting a remarkable macrocyclic effect. The high catalytic efficiency and superior stereocontrol were ascribed to the tight ion-pair binding and cavity-directed noncovalent interaction cooperation.

Mimicking the Shape and Function of the ClC Chloride Channel Selective Pore by Combining a Molecular Hourglass Shape with Anion-π Interactions.

ClC is the main family of natural chloride channel proteins that transport Cl- across the cell membrane with high selectivity. The chloride transport and selectivity are determined by the hourglass-shaped pore and the filter located in the central and narrow region of the pore. Artificial unimolecular channel that mimics both the shape and function of the ClC selective pore is attractive, because it could provide simple molecular model to probe the intriguing mechanism and structure-function relevance of ClC. Here we elaborated upon the concept of molecular hourglass plus anion-π interactions for this purpose. The concept was validated by experimental results of molecular hourglasses using shape-persistent 1,3-alternate tetraoxacalix[2]arene[2]triazine as the central macrocyclic skeleton to control the conductance and selectivity, and anion-π interactions as the driving force to facilitate the chloride dehydration and movement along the channel.

A non-residue surface modification strategy for active-targeting fluorescent silica nanoparticles to cellular organelles.

Silica nanoparticles (SiNPs) with a chemically modified surface typically have a complicated chemical composition, which can significantly differ from their intended design. In this study, we systematically studied the effects of two surface modification methods on active-targeting of intracellular organelles of SiNPs: (1) the widely used step-by-step approach, which involves modifying SiNPs in two steps, i.e., the outer surface of SiNPs was firstly modified with amino groups and then these amino groups were linked with targeting groups, and (2) a newly developed one-step approach in which the ligand-silane complex is initially synthesized, followed by chemically immobilizing the complex on the surface of SiNPs. In the one-step approach, the molar ratio of reactants was precisely tuned so that there are no reactive groups left on the outer surface of SiNPs. Two essential organelles, mitochondria and the nucleus, were selected to compare the targeting performances of SiNPs synthesized via these two approaches. By characterizing physicochemical properties, including structural properties, the number of amino groups, surface charge, polydispersity, and cell colocalization, we demonstrated that SiNPs synthesized via the one-step approach with no residual linkage groups on their surface showed significantly improved mitochondria- and nucleus-targeting performances. This precise control of surface properties allows for optimized biological behavior and active-targeting efficiency of SiNPs. We anticipate that such simple and efficient synthetic strategies will enable the synthesis of effective SiNPs for active-targeting organelles in various biological applications.

Diagnostic and Prognostic Markers for Pancreatitis and Pancreatic Ductal Adenocarcinoma.

Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.

Impact of Asp/Glu-ADP-ribosylation on protein-protein interaction and protein function.

PARylation plays critical role in regulating multiple cellular processes such as DNA damage response and repair, transcription, RNA processing, and stress response. More than 300 human proteins have been found to be modified by PARylation on acidic residues, that is, Asp (D) and Glu (E). We used the deep-learning tool AlphaFold to predict protein-protein interactions (PPIs) and their interfaces for these proteins based on coevolution signals from joint multiple sequence alignments (MSAs). AlphaFold predicted 260 confident PPIs involving PARylated proteins, and about one quarter of these PPIs have D/E-PARylation sites in their predicted PPI interfaces. AlphaFold predictions offer novel insights into the mechanisms of PARylation regulations by providing structural details of the PPI interfaces. D/E-PARylation sites have a preference to occur in coil regions and disordered regions, and PPI interfaces containing D/E-PARylation sites tend to occur between short linear sequence motifs in disordered regions and globular domains. The hub protein PCNA is predicted to interact with more than 20 proteins via the common PIP box motif and the structurally variable flanking regions. D/E-PARylation sites were found in the interfaces of key components of the RNA transcription and export complex, the SF3a spliceosome complex, and H/ACA and C/D small nucleolar ribonucleoprotein complexes, suggesting that systematic PARylation have a profound effect in regulating multiple RNA-related processes such as RNA nuclear export, splicing, and modification. Finally, PARylation of SUMO2 could modulate its interaction with CHAF1A, thereby representing a potential mechanism for the cross-talk between PARylation and SUMOylation in regulation of chromatin remodeling.

PARP1 inhibitors induce pyroptosis via caspase 3-mediated gasdermin E cleavage.

The identification of PARP1 as a therapeutic target for BRCA1/2-deficient cells has led to a paradigm shift for the treatment of human malignancies with BRCA1/2 mutations. However, our understanding of the mechanism of action of PARP1 inhibitors (PARPi) is still evolving. It is being increasingly appreciated that the immunomodulatory function of PARPi is a critical contributor of the anti-tumor effects of these compounds. Here, we identify a novel cell death effector pathway for PARPi where PARPi induces inflammatory pyroptosis that is mediated by caspase 3-dependent cleavage of GSDME. Caspase 3 is activated upon PARPi treatment which directly cleaves GSDME and, subsequently induces pyroptosis. Genetic and pharmacological experiments show that the presence of the PARP1 protein with uncompromised DNA binding capability is required for PARPi-induced pyroptosis, suggesting that PARP1 trapping is a key driver of this phenomenon. Importantly, we show that PARPi-induced GSDME cleavage and pyroptosis occurred only in the BRCA1-deficient cells, but not in those reconstituted with BRCA1 wild-type (WT). These findings suggest that pyroptosis could be a novel aspect of the immunomodulatory function of PARPi. Our studies could also offer new insights to the potential biomarkers and therapeutic strategies to achieve better anti-tumor effects of PARPi for BRCA-deficient tumors with low GSDME expression.

Atomic-scale observation of non-classical nucleation-mediated phase transformation in a titanium alloy.

Two-phase titanium-based alloys are widely used in aerospace and biomedical applications, and they are obtained through phase transformations between a low-temperature hexagonal closed-packed α-phase and a high-temperature body-centred cubic ß-phase. Understanding how a new phase evolves from its parent phase is critical to controlling the transforming microstructures and thus material properties. Here, we report time-resolved experimental evidence, at sub-ångström resolution, of a non-classically nucleated metastable phase that bridges the α-phase and the ß-phase, in a technologically important titanium-molybdenum alloy. We observed a nanosized and chemically ordered superstructure in the α-phase matrix; its composition, chemical order and crystal structure are all found to be different from both the parent and the product phases, but instigating a vanishingly low energy barrier for the transformation into the ß-phase. This latter phase transition can proceed instantly via vibrational switching when the molybdenum concentration in the superstructure exceeds a critical value. We expect that such a non-classical phase evolution mechanism is much more common than previously believed for solid-state transformations.

Intermolecular n→π* Interactions Based on a Tailored Multicarbonyl-Containing Macrocycle.

Towards unexplored intermolecular n→π* interactions, presented herein are the synthesis, structure, self-assembly and function of a multicarbonyl-containing macrocycle calix[2]arene[2]barbiturate 1. X-ray single crystal diffraction reveals the presence of Cl⋅⋅⋅C=O interactions in CH2 Cl2 ⊂1 host-guest complex and multiple intermolecular C=O⋅⋅⋅C=O interactions between molecules 1 in crystalline state. The intermolecular C=O⋅⋅⋅C=O interactions as attractive driving force led to unprecedented self-assembly of nanotube with diameter around 1.4 nm and inner surface engineered by aromatic rings. SEM and TEM images of the self-assembly of 1 demonstrated temperature-dependent morphologies which allows the observation of spheres at 25 °C and rods at 0 °C, respectively. XRD analysis indicated consistent hexagonal patterns in the self-assembly and single crystal lattice, indicating the nanotubes driven by C=O⋅⋅⋅C=O interactions constitute the basic structural architectures of both aggregates. The nanoscopic tubes (pores) formed in the rodlike single crystal engendering the separation of moving dyes were preliminarily investigated by a single-crystal chromatography and crystal-packed column chromatography.

mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.

LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5'TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1's translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation, but only in conditions of mTORC1 inhibition.

Extracorporeal cardiopulmonary resuscitation versus conventional cardiopulmonary resuscitation for patients with refractory out-of-hospital cardiac arrest: A retrospective propensity matching analysis.

OBJECTIVE: The incidence of out-of-hospital cardiac arrest (OHCA) is high. Though extracorporeal cardiopulmonary resuscitation (ECPR) has been considered a potential treatment for refractory cardiac arrest after failure of conventional cardiopulmonary resuscitation (CCPR), the benefit of ECPR in refractory OHCA remains uncertain. METHODS: In this retrospective cohort study, we included patients with refractory OHCA who visited the Emergency Department of the Aerospace Center Hospital between January 2018 and April 2023. We divided the patients into the ECPR Group and the CCPR Group. The primary endpoint of the study was the neurological function of the patients in both groups 3 months after the cardiac arrest. We used propensity score matching to reduce selection bias and identified factors associated with good neurological function when OHCA was treated with ECPR by performing univariate and multivariate correlation analyses on surviving patients with good neurological function in the ECPR group. RESULTS: During the study period, we enrolled 133 patients, consisting of 33 in the ECPR group and 100 in the CCPR group. The survival rate of patients with good neurological function at discharge was 18.2% (6/33 cases) in the ECPR group and 9% (9/100 cases) in the CCPR group, p = .20. Three months after discharge, the survival rate of patients with good neurological function was 15.2% (5/33 cases) in the ECPR group and 8% (8/100 cases) in the CCPR group, p = .31. Using propensity score matching, we identified 22 pairs of patients for further analysis. Among these, 3 months after discharge, the survival rate of patients with good neurological function was 13.6% (3/22 cases) in the ECPR group and 4.5% (1/22 cases) in the CCPR group, p = .61, and the survival rate at discharge was 18.2% (4/22 cases) in the ECPR group and 4.5% (1/22 cases) in the CCPR group, p = .34. The univariate analysis of patients with good neurological function in the ECPR group showed that time without perfusion, hypoperfusion time, and PCI treatment were associated factors affecting the prognosis of neurological function in patients, while multivariate analysis showed that hypoperfusion time was independently associated with good neurological function, with an OR (95% CI) of 1.06 (1.00-1.14) and p = .05. CONCLUSION: Our findings suggested that ECPR failed to significantly improve neurological outcome in patients with refractory OHCA; however, the small sample size in this study may be insufficient to detect clinically relevant differences. In addition, hypoperfusion time may be a key predictive factor in identifying candidates for ECPR.

Evaluation and prediction of ecological carrying capacity in the Qilian Mountain National Park, China.

With increasing human impacts on the ecosystem in natural protected areas, there is an urgent need to undertake an assessment of ecological carrying capacity taken as a benchmark for assessing regional sustainability. Based on satellite remote sensing and socio-economic statistical data from 2000 to 2019, this study distinguished the controlling factors for the spatial and temporal patterns of ecological carrying capacity in the Qilian Mountain National Park, one of the 10 pilot national parks in China. The ecological carrying capacity index (ECCI) was developed by using the Driver-Pressure-State-Impact-Response framework and a comprehensive weight method. The results showed that the multiyear averaged ECCI was low in the south and west but was high in central and eastern regions. The spatial distribution of the ECCI was constrained by soil resources, ecosystem quality, land use/cover and water environment. At the regional scale, the ECCI decreased from 2000 to 2014, especially in Tianzhu, where farmland expansion and severe droughts reduced habitat quality and ecosystem function. However, the ECCI increased significantly from 2014 to 2019, which was attributed to a warm moist climate and the implementation of eco-environmental protection policies. Forest and grassland coverage, soil and water conservation, waste water treatment amount and terrestrial water reserves accounted for 35%, 26%, 20% and 8%, respectively, of the temporal variability in the ECCI. Concurrent with national park development, the ECCI is predicted to increase in most areas from 2020 to 2029 by back-propagation artificial neural networks, except for Sunan, Shandan and Menyuan, possibly owing to increasing conflicts between humans and the environment. The findings of this study provide evidence about the effectiveness of government policies in promoting regional sustainability by altering ecosystem composition and function. In addition, the dominant drivers for the temporal variability of ecological carrying capacity varied in space according to stepwise regression analysis, calling for region-specific management strategies in mountain protected areas and their surroundings.

An Artificial Single Molecular Channel Showing High Chloride Transport Selectivity and pH-Responsive Conductance.

Inspired by the unique structure and function of the natural chloride channel (ClC) selectivity filter, we present herein the design of a ClC-type single channel molecule. This channel displays high ion transport activity with half-maximal effective concentration, EC50 , of 0.10 µM, or 0.075 mol % (channel molecule to lipid ratio), as determined by fluorescent analysis using lucigenin-encapsulated vesicles. Planar bilayer lipid membrane conductance measurements indicated an excellent Cl- /K+ selectivity with a permeability ratio P Cl - ${{_{{\rm Cl}{^{- }}}}}$ /P K + ${{_{{\rm K}{^{+}}}}}$ up to 12.31, which is comparable with the chloride selectivity of natural ClC proteins. Moreover, high anion/anion selectivity (P Cl - ${{_{{\rm Cl}{^{- }}}}}$ /P Br - ${{_{{\rm Br}{^{- }}}}}$ =66.21) and pH-dependent conductance and ion selectivity of the channel molecule were revealed. The ClC-like transport behavior is contributed by the cooperation of hydrogen bonding and anion-π interactions in the central macrocyclic skeleton, and by the existence of pH-responsive terminal phenylalanine residues.

Direct Arylation of Silicon Nanocrystals with Hexadehydro-Diels-Alder-Derived Benzynes.

Colloidal silicon nanocrystals (SiNCs) have garnered significant interest in optoelectronics and biomedical applications. Direct arylation provides pathways to enhance the solution processability of particles and manipulate the photophysical and electronic properties of SiNCs. Unfortunately, existing methods employed to prepare aryl-functionalized SiNCs are based on organometallic coupling or transition-metal-catalyzed strategies, which require metal-based reagents for preactivation or the precursors and complicated post-treatment processes for product purification. Herein, we demonstrate a metal-free method that directly functionalizes SiNCs with aryl-based ligands. We design a series of benzyne derivatives formed from the thermal cyclization of predesigned alkynes, allowing efficient arylation on hydride-terminated silicon surfaces under mild conditions. These aryl-functionalized SiNCs exhibit strong blue emissions with nanosecond-scaled decay, suggesting the formation of a new radiative recombination channel on SiNC surfaces.

Icosidodecahedral Coordination-Saturated Cuprofullerene.

The first coordination-saturated buckyball with a C60 molecule totally encased in an icosidodecahedral Cu30 in a (µ30 -(η2 )30 )-fashion, namely C60 @Cu30 @Cl36 N12 , has been successfully realized by a C60 -templated assembly. The 48 outmost coordinating atoms (36Cl+12N) comprise a new simple polyhedron that is described by a ccf topology. Charge transfer from (CuI , Cl) to C60 explains the expansion of the light absorption up to 700 nm, and accounts for an ultrafast photophysical process that underpins its high photothermal conversion efficiency. This work makes a giant step forward in exohedral metallofullerene (ExMF) chemistry.

Fully Reversible Ratiometric Nanosensors for Continuously Quantifying Mitochondrial Glutathione Concentration in Living Cells.

Mitochondrial glutathione (mGSH) is both the cause of the oxidative damage and a mechanism for maintaining the redox homeostasis in mitochondria. To effectively measure mGSH dynamics in living cells, we have developed a new FRET-based nanosensor by immobilizing rhodamine B into dendritic mesoporous silica nanoparticles and installing GSH probes and mitochondria-targeting motifs onto the surface of nanoparticles. The result shows that these nanosensors show efficient FRET and a full reversibility and rapid response (<10 s) to GSH in the range of 0.5-20 mM, due to their unique nanostructure and well-overlapped spectra. The excellent photostability and low cytotoxicity make them an effective means for monitoring mGSH concentration in real time. When the mGSH nanosensors are used for quantitatively measuring mGSH variations under glucose deprivation stimulation in HeLa cells, they successfully prove themselves a useful tool for mitochondrial redox activity studies.

The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1.

Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the higher binding affinity of TAK1 and p38IP for polyUb-bound TAB2 and TAK1, respectively. Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.