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Abstract Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3–METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239–580 of METTL3). We find that METTL3a is required for the METTL3–WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3–METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a–mTOR axis as a potential therapeutic target for breast cancer.

Abstract Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

The acetyltransferase Tip60 mediates signaling pathways by acetylating non-histone proteins. Here the authors show that fatty acids induce Tip60–dependent acetylation of phosphatidic acid phosphatase lipin1 which, then, translocates to the ER and generates diacylglycerols for triglyceride synthesis.

The important MAPK family of signalling proteins is controlled by MAPK phosphatases (MKPs). Here, the authors report the structure of MKP7 bound to JNK1 and characterise the conserved MKP-MAPK interaction.

Water−rock interactions can alter rock properties through chemical reactions during subsurface transport processes like geological CO2 sequestration (GCS), matrix acidizing, and waterflooding in carbonate formations. Dynamic changes in rock properties cause a failure of waterflooding and GCS and could also dramatically affect the efficiency of the acidizing. Efficient numerical simulations are thus essential to the optimized design of those subsurface processes. In this paper, we develop a three-dimensional (3D) numerical model for simulating the coupled processes of fluid flow and chemical reactions in fractured carbonate formations. In the proposed model, we employ the Stokes−Brinkman equation for momentum balance, which is a single-domain formulation for modeling fluid flow in fractured porous media. We then couple the Stokes−Brinkman equation with reactive-transport equations. The model can be formulated to describe linear as well as radial flow. We employ a decoupling procedure that sequentially solves the Stokes−Brinkman equation and the reactive transport equations. Numerical experiments show that the proposed method can model the coupled processes of fluid flow, solute transport, chemical reactions, and alterations of rock properties in both linear and radial flow scenarios. The rock heterogeneity and the mineral volume fractions are two important factors that significantly affect the structure of conductive channels.