Video Experimental Relacionado

Updated: May 5, 2026

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

Published on: January 6, 2017

El represor transcripcional Fli1 inhibe la proteostasis durante el estrés nutricional para limitar la persistencia de

Jeong Hyun Ji¹, Wesley R Armstrong², Joey H Li²

¹Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.

|February 19, 2026

Abstract:

Tumor-infiltrating natural killer (NK) cells display reduced persistence and effector functions. Here, we examined the mechanisms underlying NK cell dysfunction in cancer. Gene expression analyses of matched tumor-infiltrating and tumor-adjacent human NK cells revealed that regulators of proteostasis were associated with worse survival outcomes. In mice, NK cells accumulated intracellular protein aggregates within 24 h of tumor infiltration. Nutrient stress in the tumor microenvironment (TME) triggered proteostasis imbalance in primary human NK cells, decreasing translation of cytokine receptors and inhibiting NK cell activation. SCENIC regulon and multiomic analyses identified FLI1 as a transcriptional repressor of the unfolded protein response (UPR) in NK cells. FLI1 induction following IL-15 signaling suppressed pro-survival UPR gene expression, limiting human NK cell proteostasis and intra-tumoral persistence. Fli1 deletion reduced protein aggregates and enhanced NK cell-mediated tumor control in vivo. Thus, the TME metabolome induces NK cell dysfunction through proteostasis imbalance, and FLI1 targeting may enhance NK cell anti-tumor function.

Palabras clave:

Fli1 disfunción metabolismo células natural killer agregado de proteínas proteostasis tumores sólidos líquido intersticial tumoral microambiente tumoral respuesta a proteínas mal plegadas

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