Molecular and Functional Analysis of TXNDC11 in Neuro2a Neuroblastoma Cells: A Potential Drug Target in ER Stress-Associated Disorders

Akane Kanamori, Yuga Nagamoto, Mahmoud Kandeel and Kentaro Oh-hashi

Background and Objective: Thioredoxin-Domain Containing 11 (TXNDC11), a member of the thioredoxin superfamily, is suggested to interact with EDEM2 and is implicated in the modulation of ERAD processes. However, reports on its expression and function are limited. This study investigates the role of TXNDC11 in the regulation of endoplasmic reticulum (ER) stress responses and ER-associated degradation (ERAD) in Neuro2a neuroblastoma cells. Materials and Methods: The CRISPR/Cas9 technology was applied to generate TXNDC11-deficient Neuro2a cell lines to explore the protein's influence on cellular responses under stress conditions induced by agents such as thapsigargin (Tg), tunicamycin (Tm) and brefeldin A (BFA). Statistical analysis of changes in the expression of each mRNA and protein is carried out using one-way ANOVA followed by the Tukey-Kramer test. Results: The study findings indicated that TXNDC11 deficiency does not significantly alter the transcriptional response of classical ER stress markers (ATF3, GADD153, GRP78, Herp and sXBP1) but does lead to increased expression of the ER-phagy receptor FAM134B, suggesting a compensatory mechanism within the ER-phagy pathway. Furthermore, comparative proteomic analysis showed a marked decrease in EDEM2 protein levels, suggesting a specific role of TXNDC11 in modulating the activity of ER-localized mannosidases involved in N-glycoprotein degradation. Moreover, the differential expression of ERAD and ER-phagy components in TXNDC11-deficient cells highlights the balance between protein folding, degradation and cellular homeostasis. Conclusion: This study on TXNDC11 and FAM134B expression analysis suggests that ERAD and ER-phagy are associated with ER homeostasis under pathophysiological conditions. Furthermore, examining the interaction between TXNDC11 and FAM134B could be valuable as a potential biomarker in neurodegenerative diseases and cancers.

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