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Endoplasmic Reticulum Stress Causes Thyroglobulin Retention in this Organelle and Triggers Activation of Nuclear Factor-B Via Tumor Necrosis Factor Receptor-Associated Factor 2

Dipartimento di Biologia e Patologia Cellulare e Molecolare (A.L., C.M., L.U., S.F.), BioGem Consortium (P.V.), Centro di Endocrinologia e Oncologia Sperimentale (F.P., E.C.), Federico II, University of Naples, 80100 Naples, Italy; and Laboratorio di Patologia Generale, Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Lecce (B.D.J.), 73100 Lecce, Italy

Address all correspondence and requests for reprints to: Dr. Bruno Di Jeso, Laboratorio di Patologia Generale, Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Facoltà di Scienze MFN, Strada Lecce-Monteroni, Università degli Studi di Lecce, 73100 Lecce, Italy. E-mail: . bdijeso{at}ilenic.unile.it

Perturbing the endoplasmic reticulum homeostasis of thyroid cell lines with thapsigargin, a specific inhibitor of the sarco-endoplasmic reticulum Ca²⁺ adenosine triphosphatases, and tunicamycin, an inhibitor of the N-linked glycosylation, blocked Tg in the endoplasmic reticulum. This event was signaled outside the endoplasmic reticulum and resulted in activation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase and nuclear factor-B (NF-B) stress response pathways. Activation of the JNK/stress-activated protein kinase signaling pathway was assessed by measuring the amount of phospho-JNK and the activity of JNK by kinase assays. Activation of the NF-B signaling pathway was assessed by measuring the level of inhibitory subunit IB, DNA binding, and transcriptional activity of NF-B. Cycloheximide treatment, at a dose able to profoundly inhibit protein synthesis in FRTL-5 cells, obliterated the decrease in the level of the inhibitory subunit IB produced by thapsigargin and tunicamycin. Therefore, protein synthesis was required to generate a signal from stressed endoplasmic reticulum. This substantiates the hypothesis that endoplasmic reticulum retention of newly synthesized Tg and other cargo (secretory and membrane) proteins functions upstream of signal activation. Dominant negative TNF receptor-associated factor 2 (TRAF2) inhibited activation of NF-B, which was also inhibited in embryonic fibroblasts derived from TRAF2^-/- mice, respect to their normal counterpart. These data extend the recent demonstration that TRAF2 mediated JNK activation in response to endoplasmic reticulum stress and strongly strengthened the idea that endogenous stress signals initiated in the endoplasmic reticulum proceed by a pathway similar to that initiated by plasma membrane receptors in response to extracellular signals.

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