Work

TRIM21 licenses pancreatic acinar fate by modulating BiP phase state through VCP-dependent retrotranslocation

Year: 2026

Type: preprint

Abstract: ABSTRACT The endoplasmic reticulum (ER) chaperone BiP/GRP78 sits at the center of the proteostasis network, coordinating unfolded protein response (UPR) signaling and supporting oncogenic programs of plasticity, metastasis, immune evasion, and chemoresistance. While BiP undergoes liquid–liquid phase separation in vitro, whether mammalian cells dynamically tune this physicochemical behavior to prevent functional exhaustion or pathological condensation under sustained ER stress has remained unclear. Here, we identify the E3 ubiquitin ligase TRIM21 as a phase-state regulator that suppresses BiP’s liquid-to-solid phase separation, clearing, and preventing insoluble aggregates—thereby controlling BiP’s localization and availability to sustain the adaptive UPR under ER stress. We found that during ER stress, BiP is prone to liquid-to-solid phase separation, a transition that renders the chaperone dysfunctional. TRIM21 is recruited to BiP, where it directly polyubiquitinates BiP at specific K547/553/554/556 sites with K6-, K27-, K33-, and K63-linked chains; VCP recognizes these marks and extracts BiP from the ER lumen via ER-associated degradation (ERAD), coupling ubiquitin tagging to retrotranslocation. This preserves chaperone availability and sustains adaptive UPR—a homeostatic mechanism broadly relevant to UPR-driven diseases. In vivo, genetic ablation of Trim21 in Kras G12D/+ ; Pdx1 Cre/+ mice triggers aberrant BiP solidification while curtailing acinar-to-ductal transdifferentiation and tumorigenesis; notably, TRIM21 co-localizes with BiP condensates in pre-malignant human pancreatic lesions, underscoring the clinical relevance of this regulatory axis. Our findings define the TRIM21-BiP axis as a phase-control system at the interface of proteostasis and stress adaptation, offering a new framework with translational potential. Significance statement BiP phase separation is controlled by ubiquitin-dependent retrotranslocation, linking the UPR machinery to oncogenic reprogramming. We identify TRIM21 as a phase-state rheostat of the ER chaperone BiP and show that the TRIM21–BiP axis defines an unexpected interface between proteostasis and stress adaptation, revealing BiP phase behavior as a potential therapeutic target in early-stage pancreatic cancer.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.29.755563