Biology subjects

Tan, J. M.

Publications and source records attributed to Tan, J. M..

4 recordsLinked to original sources

bioRxiv2026

SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast-like State to Drive Metabolic Disease

Pathogenic adipose tissue remodeling promotes metabolic disease in obesity, but the mechanisms that establish this unhealthy tissue state remain poorly understood. Here, we show that obesity drives SOX4-dependent reprogramming of mesenchymal stromal cells (MSCs) into cancer-associated fibroblast-like (CAF-like) cells that promote adipose tissue dysfunction. TGF{beta} signaling is elevated in obesity and activates SOX4 in mouse and human MSCs, inducing their conversion to a CAF-like state. In mice, MSC-specific SOX4 activation induces the CAF-like program and exacerbates adipose tissue inflammation and glucose intolerance, whereas Sox4 deletion attenuates inflammation and improves glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector produced by CAF-like cells. MDK inhibition in obese mice reduces adipose tissue inflammation and improves metabolic function. Together, these findings define a TGF{beta}-SOX4-MDK stromal signaling axis that drives pathological adipose tissue remodeling in obesity and highlight this pathway as a potential therapeutic target for improving metabolic health.

cell biology↗

bioRxiv2026

Human interferon stimulated genes target ancient features of animal and bacterial viral replication

Animal and bacterial cells defend against viral infection by rapidly activating antiviral restriction factors. In human cells, antiviral immunity is initiated by interferon signaling that results in expression of hundreds of interferon-stimulated genes (ISGs)1,2,3,4,5,6. Complex regulatory networks and co-evolution of viral evasion strategies complicate analysis of immune proteins under native conditions and the function of most individual ISGs remains unknown7,8,9,10,11,12. Here we discover that heterologous expression of ISGs in bacteria is sufficient to protect against infection by diverse bacteriophages demonstrating properties of antiviral restriction preserved across billions of years of viral evolution. A screen of 306 human ISGs against 11 E. coli phages reveals that ISGs can restrict phage replication with potency equal to endogenous bacterial defense systems. We select for phage mutants that escape ISG restriction and identify the phage DNA primase-helicase complex as a target of human SPSB1. A 2.0 [A] crystal structure of the SPSB1-primase complex uncovers a recognition mechanism of foreign DxNxN protein motifs found in many animal and bacterial viral replication proteins. We show that SPSB1 in human cells recognizes and induces degradation of protein targets containing this motif from norovirus and poxvirus pathogens. Our results establish a cross-kingdom approach to studying immune function and reveal that human ISGs target features of viral replication common across kingdoms of life.

immunology↗

bioRxiv2024

Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease

The emergence of A{beta} pathology is one of the hallmarks of Alzheimers disease (AD), but the mechanisms and impact of A{beta} in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope and its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of A{beta} on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses A{beta} in young animals. Our studies revealed that a time-dependent accumulation of intracellular A{beta} corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction App KI neurons become more vulnerable to inflammation-induced necroptosis - a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates A{beta} in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.

neuroscience↗

bioRxiv2020

Associative Learning and Motivation Differentially Requires Neuroligin-1 at Excitatory Synapses

In a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Understanding how these decision-making processes and underlying neural computations are orchestrated by the structural components of the brain, from circuits to cells, and ultimately the signaling complex of proteins at synapses, is central to elucidating the mechanisms that shape normal and abnormal brain connectivity, plasticity and behavior. At excitatory synapses, neuroligin-1 (Nlgn1) a postsynaptic cell-adhesion molecule required for the formation of trans-synaptic complexes with presynaptic partners is critical for regulating synapse specification, function and plasticity. Extensive evidence shows Nlgn1 is essential for synaptic transmission and long-term plasticity, but how these signaling processes ultimately regulate components of cognitive behavior is much less understood. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we measured two key decision problems: i) the ability to learn and exploit the associative structure of the environment and ii) the trade-off between potential rewards and costs, or positive and negative utilities associated with available actions. We found that mice lacking Nlgn1 have an intact capacity to acquire complex associative structures and adjust learned associations. However, loss of Nlgn1 alters motivation leading to a reduced willingness to overcome response effort for reward and an increased willingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off. Our findings identify Nlgn1 is essential for regulating distinct cognitive processes underlying decision-making, providing evidence of a new model for dissociating the computations underlying learning and motivational processing.

neuroscience↗