Biology subjects

Ko, M. S.

Publications and source records attributed to Ko, M. S..

4 recordsLinked to original sources

bioRxiv2026

Cryo-EM reveals alternative modes of dimerization driving activation of IKK

The inhibitor of {kappa}B kinase (IKK) complex integrates diverse cellular inflammatory responses, and induces transcription factor NF-{kappa}B. The molecular mechanism by which IKK becomes catalytically active in response to signaling remains unclear despite structural knowledge of the individual IKK1/, IKK2/{beta}, and NEMO/IKK{gamma} protein components within its hetero-oligomeric assembly. Cryo-EM of the IKK2/{beta} homodimer bound to an associating NEMO/IKK{gamma} protein fragment, reveals multiple conformers. Mutual exclusivity of dimeric conformers, canonical versus alternate, is reflected in and dependent upon order-to-disorder transition of the canonical 6-helical bundle dimerization interface. Correlation of this unusual structural plasticity of IKK2/{beta} with its biochemical and cellular activities suggests mechanistic possibilities for how association with its partner scaffold protein NEMO/IKK{gamma} and polyubiquitin chains might dictate catalytic activation of IKK through distinct IKK2/{beta} conformers. SignificanceThe inhibitor of {kappa}B kinase (IKK) complex is central to inflammatory signaling via the NF-{kappa}B family transcription factors. Its activation mechanism has remained unclear. Cryo-EM analysis reveals that the constituent kinase IKK2/{beta} adopts structurally distinct, mutually exclusive dimeric conformations controlled by an ordered-to-disordered transition at its canonical dimerization interface. Stabilization of select IKK2/{beta} conformers by the scaffold protein NEMO in association with poly-ubiquitin chains is regulated through modular architecture and structural plasticity of distinctive kinase-associated domains, present only in kinases of this family. This unique regulatory mechanism governing catalytic activation of IKK2/{beta} provides a conceptual framework for targeting dysregulated NF-{kappa}B signaling in human diseases.

immunology↗

bioRxiv2026

Lipogenesis-driven EGFR palmitoylation enables metastatic immune evasion in triple-negative breast cancer.

Metastasis is the leading cause of death in triple-negative breast cancer (TNBC), yet how tumor cells evade immune recognition during dissemination remain unclear. Here, we show that de novo lipogenesis drives metastatic immune evasion through FASN-mediated palmitoylation of EGFR. This modification establishes a lipid-dependent membrane signaling scaffold that sustains PI3K-AKT-mTOR signaling independently of MAPK compensation, thereby suppressing MHC-I antigen presentation through post-translational regulation. As a result, metastatic-competent cells escape CD8+ T cell surveillance and colonize distant organs. Genetic or pharmacologic inhibition of fatty acid synthase (FASN), or expression of palmitoylation-deficient EGFR mutants restores MHC-I surface expression, unleashes robust CD8 T cell activation, and markedly impairs lung metastasis without affecting primary tumor growth. This lipid-dependent EGFR-PI3K-mTOR axis operates independently of MAPK signaling and is not rescued by exogenous lipids, revealing a non-redundant metabolic dependency. Our results identify FASN-driven EGFR palmitoylation as a tumor-intrinsic immunometabolic checkpoint that couples lipid metabolism to antigen-presentation and metastatic competence. Targeting this pathway with clinically advancing FASN inhibitors offers a promising strategy to suppress metastasis by restoring anti-tumor immunity in TNBC.

cancer biology↗

bioRxiv2025

Functional redundancy between UTY and UTX in regulating the localization of transcription factors involved in pluripotency

The Y chromosome harbors few protein-coding genes, and their roles in early human development remain largely unclear. Here, we demonstrate that UTY, a Y-linked homolog of the histone demethylase UTX, plays a critical, demethylase-independent role in maintaining pluripotency in human embryonic stem cells (hESCs). Despite its low expression and weak enzymatic activity, UTY co-occupies active cis-regulatory elements with UTX and promotes the transcription of key pluripotency genes, including NODAL and LEFTY. Integrated genomic analyses of single and double knockout hESCs reveal that UTY and UTX function redundantly to maintain chromatin accessibility and ensure proper recruitment of core transcription factors such as OCT4 and SOX2. The combined loss of UTY and UTX disrupts transcription factor localization, induces widespread gene expression changes, and leads to a collapse of the pluripotent state, without detectable changes in H3K27 methylation. Instead, these defects are associated with impaired recruitment of ATP-dependent chromatin remodelers and reduced histone acetylation, suggesting a demethylase-independent mechanism. Our findings uncover an essential role for the evolutionarily conserved UTY in safeguarding enhancer function and transcription factor occupancy, highlighting Y-linked regulatory mechanisms that are critical for maintaining human pluripotency. Summary statementThis study reveals how UTX and UTY cooperate to maintain stable gene regulation in human stem cells and guide proper developmental programs.

developmental biology↗

bioRxiv2016

Tracking stem cell differentiation without biomarkers using pattern recognition and phase contrast imaging

Bio-image informatics is the systematic application of image analysis algorithms to large image datasets to provide an objective method for accurately and consistently scoring image data. Within this field, pattern recognition (PR) is a form of supervised machine learning where the computer identifies relevant patterns in groups (classes) of images after being trained on examples. Rather than segmentation, image-specific algorithms or adjustable parameter sets, PR relies on extracting a common set of image descriptors (features) from the entire image to determine similarities and differences between image classes.\n\nGross morphology can be the only available description of biological systems prior to their molecular characterization, but these descriptions can be subjective and qualitative. In principle, generalized PR can provide an objective and quantitative characterization of gross morphology, thus providing a means of computationally defining morphological biomarkers. In this study, we investigated the potential of a pattern recognition approach to a problem traditionally addressed using genetic or biochemical biomarkers. Often these molecular biomarkers are unavailable for investigating biological processes that are not well characterized, such as the initial steps of stem cell differentiation.\n\nHere we use a general contrast technique combined with generalized PR software to detect subtle differences in cellular morphology present in early differentiation events in murine embryonic stem cells (mESC) induced to differentiate by the overexpression of selected transcription factors. Without the use of reporters, or a priori knowledge of the relevant morphological characteristics, we identified the earliest differentiation event (3 days), reproducibly distinguished eight morphological trajectories, and correlated morphological trajectories of 40 mESC clones with previous micro-array data. Interestingly, the six transcription factors that caused the greatest morphological divergence from an ESC-like state were previously shown by expression profiling to have the greatest influence on the expression of downstream genes.

cell biology↗