HSPB8 regulates CTP synthase filaments to couple nucleotide metabolism and autophagy in tumors
Abstract
Metabolic adaptation and proteostasis are essential for tumor survival under nutrient stress, yet how these processes are mechanistically integrated remains unclear. Here, we identify CTP synthase (CTPS) filament dynamics as a regulatory nexus linking nucleotide metabolism to autophagic flux. Under glutamine deprivation--a hallmark of poorly vascularized solid tumors--CTPS undergoes polymerization into filamentous assemblies that exhibit reduced enzymatic activity. We demonstrate that filament formation is driven by intracellular asparagine availability and stabilized by the accumulation of misfolded proteins. Using APEX2-based proximity labeling and proteomics, we identify the small heat shock protein HSPB8 as a filament-associated regulator. HSPB8, acting within the chaperone-assisted selective autophagy (CASA) pathway, antagonizes CTPS polymerization by promoting clearance of misfolded proteins, thereby restoring soluble, catalytically active CTPS. Filament disassembly increases CTP production and enhances synthesis of autophagy-related phospholipids, including phosphatidylinositol and phosphatidylethanolamine, resulting in accelerated autophagic flux. Cells expressing filament-deficient CTPS mutants display elevated autophagosome formation and increased LC3-II accumulation upon lysosomal blockade, confirming enhanced flux. In vivo, disruption of CTPS filament assembly impairs xenograft tumor growth and is associated with excessive autophagy. Analysis of TCGA datasets further reveals that high CTPS and low HSPB8 expression correlate with poor patient survival across multiple cancers. Collectively, our findings establish CTPS filament dynamics as a proteostasis-sensitive metabolic switch that coordinates nucleotide biosynthesis with autophagy, revealing a previously unrecognized vulnerability in tumors adapting to nutrient limitation.
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- biorxiv v4 2026-07-09 source ↗
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bioRxiv Cell Biology @biorxiv-cellbio.bsky.social · 6030 followers neutral
HSPB8 regulates CTP synthase filaments to couple nucleotide metabolism and autophagy in tumors https://www.biorxiv.org/content/10.64898/2026.02.10.704981v1
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bioRxivpreprint @biorxivpreprint.bsky.social · 8895 followers neutral
HSPB8 regulates CTP synthase filaments to couple nucleotide metabolism and autophagy in tumors https://www.biorxiv.org/content/10.64898/2026.02.10.704981v1