Kymera Therapeutics

Duck plague, caused by the alphaherpesvirus Duck plague virus (DPV), is an acute, hemorrhagic, and economically devastating disease of waterfowl. DPV infection induces severe immunosuppression, yet the mechanisms by which this pathogen subverts host innate immunity, particularly through manipulation of the host ubiquitin system, remain unclear. The cGAS-STING signaling pathway is a cornerstone of anti-DNA viral immunity. In avian species, where IRF3 has been evolutionarily lost, the transcription factor IRF7 plays a pivotal role in activating type I interferons (IFN-I). Here, we identify duck RNF34 (DuRNF34) as a host E3 ubiquitin ligase that broadly suppresses the duck cGAS-STING pathway by targeting multiple components, including DucGAS, DuSTING, and DuIRF7, for ubiquitination and degradation. Importantly, DPV infection upregulates DuRNF34 expression, which selectively targets DuIRF7 for degradation to facilitate viral replication. Further affinity purification-mass spectrometry (AP-MS) analysis revealed that LORF2, a DPV-specific protein, recruits DuRNF34 to catalyze K11- and K48-linked polyubiquitination of DuIRF7 at lysine residues K51 and K453, leading to DuIRF7 degradation and suppression of IFN-β and downstream antiviral genes. Functional validation confirmed that siRNA-mediated knockdown of LORF2 markedly attenuated DPV-induced DuIRF7 degradation and impaired viral replication. Collectively, these findings reveal a novel immune evasion strategy in which DPV hijacks the host E3 ligase DuRNF34 via its unique protein LORF2, thereby targeting DuIRF7 for degradation to subvert innate immunity. This work provides new insights into herpesviral immune evasion and suggests potential targets for therapeutic intervention.

Interleukin 2 (IL-2) is a cytokine secreted by activated T cells that plays a central role in T cell proliferation and differentiation. In this study, we identified MARCH2, an E3 ubiquitin ligase of the MARCH family, as a negative regulator of IL-2 receptor alpha (IL-2Rα). MARCH2 interacts with IL-2Rα and catalyzes its K27-linked polyubiquitination and subsequent proteasomal degradation. Site-directed mutagenesis indicates that K267 of IL-2Rα is targeted by MARCH2 and mutation of this residue impairs MARCH2-mediated polyubiquitination and degradation of IL-2Rα. MARCH2-deficiency promotes IL-2-triggered STAT5 phosphorylation, effector gene expression, and proliferation of activated T cells. Our findings suggest that MARCH2 negatively regulates IL-2 signaling by targeting IL-2Rα for K27-linked polyubiquitination and proteasomal degradation, uncovering a post-translational mechanism that regulates T cell homeostasis.

The F-box protein ZmFBL41, which targets ZmCAD and ZmNCED6, increases susceptibility to maize banded leaf and sheath blight (BLSB). Here, we report significantly reduced BLSB resistance in maize expressing the susceptible haplotype ZmFBL41B73, and the identification of ZmFBL41B73-interacting protein, fumarylacetoacetate hydrolase (FAH). In contrast to ZmCAD, which interacts with the LRR3 motif, ZmFAH interacts with each LRR motif of ZmFBL41B73. ZmFAH positively regulates plant resistance to Rhizoctonia solani and decrease BLSB resistance in zmfah maize but increase sheath blight (ShB) resistance in ZmFAH-overexpressing rice. ZmFAH is involved in fumaric acid (FA) metabolism, which inhibits fungal growth and invasion in plants. Compared with the susceptible allele of ZmFBL41B73, the resistant haplotype ZmFBL41Chang7-2, with two amino acid substitutions, exhibits weaker interactions with and promotes the degradation of ZmFAH, thereby resulting in greater FA accumulation and increased resistance to BLSB in the inbred lines of the Chang7-2 haplotype than in those of the B73 haplotype. Additionally, field fumarate pretreatment significantly increases rice resistance to bacterial blight and ShB. Collectively, our findings reveal the dual functions of ZmFBL41Chang7-2 in strengthening the host's chemical barrier through FA accumulation in addition to the previously identified physical barrier protection through lignin accumulation during fungal infection.

AIDS (acquired immunodeficiency syndrome) is the final stage of infection with the human immunodeficiency virus (HIV) and adversely impacts the health of affected people globally, placing an added burden on healthcare systems. Nonetheless, advanced HIV infection is still not effectively curable, so the search for new drug targets remains an important research focus. Tripartite motif (TRIM) proteins constitute an extensive family of ubiquitin E3 ligases that regulate a wide range of cellular processes. Several recent studies have shown that many of TRIM proteins can take part in host defense to combat viral infection by diverse and distinct molecular mechanisms involving interaction with the NF-κB (Nuclear Factor kappa-B) pathway, JAK(Janus Kinase)-STAT (Signal Transducer and Activator of Transcription) pathway, RLR/MDA5 (Melanoma Differentiation-Associated protein 5) pathway, as well as IRF (Interferon Regulatory Factor) pathway; it can even induce premature degradation of viral proteins. Thus, this review aims to offer an in-depth insight into the roles of TRIM proteins in the pathologic progression of advanced HIV infection, especially on HIV-1 invasion and long terminal transcription inhibition and nonhistone protein reversible ubiquitination, which may afford therapeutic targets for this challenging disease.

Pyrophosphate is a byproduct of numerous cellular reactions that use ATP or other nucleoside triphosphates to synthesize DNA, RNA, protein, and various molecules. Its degradation into monophosphate is thus crucial for the survival and proliferation of all life forms. The human malaria parasite Plasmodium falciparum encodes two classes of pyrophosphatases to hydrolyze pyrophosphate. The first consists of P. falciparum proton pumping vacuolar pyrophosphatases (e.g., PfVP1), which localize to the parasite plasma membrane and work as proton pumps. The second includes P. falciparum soluble pyrophosphatases (PfsPPases), which have not been well characterized. Interestingly, the gene locus of PfsPPases encodes two isoforms, PfsPPase1 (PF3D7_0316300.1) and PfsPPase2 (PF3D7_0316300.2). PfsPPase2 contains a 51-amino acid organellar localization peptide that is absent in PfsPPase1. Here, we combine reverse genetics and biochemical approaches to identify the localization of PfsPPase1 and PfsPPase2 and elucidate their individual functions. We show that PfsPPases are essential for the asexual blood stages. While PfsPPase1 solely localizes to the cytoplasm, PfsPPase2 exhibits multiple localizations, including the mitochondrion, the apicoplast, and, to a lesser extent, the cytoplasm. Our data suggest that P. falciparum has taken a unique evolutionary trajectory in pyrophosphate metabolism by utilizing a leader sequence to direct sPPases to multiple organelles. This differs from model eukaryotes as they generally encode multiple sPPases at distinct genetic loci to facilitate pyrophosphate degradation in cytosolic and organellar compartments. The essentiality and divergence of PfsPPases also highlight them as promising targets for the development of novel antimalarial drugs. Malaria kills over 600,000 people annually. Understanding parasite biology is critical for identifying prospective drug targets. Malaria parasites maintain pyrophosphate (PPi) homeostasis in at least three subcellular compartments-the cytoplasm, mitochondrion, and apicoplast, where PPi is generated through various reactions. While cytoplasmic PPi is known to be degraded by soluble pyrophosphatase, it remains unclear how PPi is metabolized in the organelles of malaria parasites. Here, we discovered that Plasmodium falciparum encodes two soluble pyrophosphatase isoforms from a single genetic locus. The longer isoform contains an N-terminal leader sequence that targets the enzymes into the mitochondrion and the apicoplast. This dual targeting mechanism of soluble pyrophosphatases has not been previously reported in any organisms. We show that both isoforms are essential for parasite growth and development. These findings highlight the critical role of organellar PPi degradation and identify soluble pyrophosphatases as promising antimalarial drug targets.

10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe2+ levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14-3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo, 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.

Atopic dermatitis (AD) is the most common chronic inflammatory skin diseases and has traditionally been viewed as a disorder confined to the skin. However, emerging epidemiologic, genetic, and mechanistic evidence increasingly supports the concept that AD represents a systemic disease associated with a broad spectrum of immune-related comorbidities. This review synthesizes current literature on the comorbidities associated with AD, including dermatologic, respiratory, gastrointestinal, rheumatologic, neurologic, ophthalmologic, and endocrine disorders. Well-established associations include other atopic diseases such as asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis, reflecting shared type 2 inflammatory pathways and epithelial barrier dysfunction. In addition, increasing evidence links AD with non-atopic autoimmune and immune-mediated conditions, including alopecia areata, chronic spontaneous urticaria, vitiligo, psoriasis, hidradenitis suppurativa, bullous pemphigoid, inflammatory bowel disease, autoimmune thyroid disease, and several rheumatologic disorders. Epidemiologic studies suggest that the risk of autoimmune comorbidity is influenced by AD severity, age, and sex, with more severe AD associated with higher risk of comorbidities. Shared pathogenic pathways - including epithelial barrier disruption, Th2-driven immune activation, impaired immune tolerance, and autoreactive antibody responses - may underlie these associations. Recognition of these comorbidities has important implications for clinical practice, including early identification of systemic disease, multidisciplinary management, and selection of targeted therapies including biologics and Janus kinase inhibitors that may address overlapping inflammatory pathways. Improved understanding of these relationships may inform personalized treatment strategies and guide future research into shared mechanisms linking atopy and autoimmunity.