A Proteostasis Checkpoint Governs EGFR Stability and Cell Fitness, Defined by an lncRNA [RNA-seq]
The protein abundance of receptor tyrosine kinases such as EGFR is actively maintained under basal conditions by mechanisms that are distinct from ligand-induced signaling and degradation, yet the molecular basis of this regulation remains poorly understood. Here, we identify the long noncoding RNA ERBBride as a critical regulator of EGFR proteostasis. ERBBride binds the EGFR intracellular domain and prevents K48-linked ubiquitination and proteasomal degradation via a UBAP2L-PSMD1 axis. Loss of ERBBride triggers rapid EGFR degradation, robustly reversed by proteasome inhibition, establishing ERBBride as a determinant of receptor stability. This regulation occurs across diverse cancer contexts, irrespective of EGFR mutation, demonstrating mutation-agnostic control of EGFR proteostasis. Despite preserved or even enhanced canonical EGFR signaling outputs, ERBBride depletion selectively impairs EGFR-driven cellular proliferation, including in EGFR-expressing models with oncogenic KRAS backgrounds, revealing that EGFR abundance sustains cell fitness independently of acute canonical signaling. Both genetic depletion and steric-blocking antisense oligonucleotides targeting the ERBBride-EGFR interface reduce tumor growth, providing mechanistic validation and potential therapeutic modulation. Together, these findings define an lncRNA-governed proteostasis checkpoint that controls EGFR stability and cellular fitness, uncovering a previously unappreciated layer of receptor regulation with broad implications for cancer biology and therapy. Overall design: RNA-seq profiling of MDA-MB-231 cells transfected with control siRNA (siCTRL, n=3) or ERBBride-targeting siRNA-1(n=3)