Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2α kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective ER retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide bonded complexes in the ER. The protein disulfide isomerase ERp44 promotes sERr and increases the size of sERr complexes. Here we show that sERr is reversible upon washout. Pulse chase analyses show that upon recovery, only a small fraction of the sERr complexes disintegrates and contributes to the matured proteins, while most are newly synthesized. Sequential inductions of sERr and washouts demonstrate an accelerated recovery that is dependent on the unfolded protein response transducer IRE1. Since IRE1 regulates the expression level PDIA6, we analyzed its contribution to sERr. We found that PDIA6 and ERp44 constitutively interact by disulfides and have opposite effects on resumed recovery of trafficking following removal of sERr conditions. Deletion of ERp44 accelerates, while deletion of PDIA6 slows down recovery with a minimal effect on total protein synthesis. ERp44 is a primary interactor with sERr clients. When missing, PDIA6 partitions more into sERr complexes. Deletion of the tumor suppressor PTEN, which induces RTK signaling, promoted sERr formation kinetics, and accelerated the recovery, suggesting feedback between RTKs signaling and sERr. This study suggests that sERr, should develop physiologically or pathologically, is counteracted by adaptation responses that involve IRE1 and PDIA6.
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The cover of this issue of the Biochemical Journal details the close-up interface between ubiquitin-conjugating enzyme E2 (UBC2) and the Hemi-RING of mammalian ubiquitin protein ligase E3 component n-recognin 4 (UBR4). Residues at the interface are shown as sticks. Hydrogen bonds are indicated with dashes. Read more in, ‘Ubiquitin E3 ligases in the plant Arg/N-degron pathway’ from Mabbitt and Oldham on pp 1949-1965.
Opposing regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6
Olaya Yassin, Bellam Praveen, Odai Darawshi, Thomas LaFramboise, Miriam Shmuel, Shakti P. Pattanayak, Brian K. Law, Maria Hatzoglou, Boaz Tirosh; Opposing regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6. Biochem J 18 December 2024; 481 (24): 1921–1935. doi: https://doi.org/10.1042/BCJ20240444
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