Impact of GADD34 on Apoptosis of Tonsillar Mononuclear Cells from IgA Nephropathy Patients by Regulating Eif2α Phosphorylation

Abstract

Background/Aims: Tonsillectomy may be an important method to achieve a long-term remission of IgAN, but patients’ physical status may limit their access to this surgery. We proposed an encouraging solution through inhibiting GADD34 expression in order to promote tonsillar mononuclear cells (TMCs) apoptosis and reduce nephropathic IgA secretion. Methods: A total of 12 IgAN and 9 non-IgAN patients were involved from March 2015 to May 2016. After TMCs were extracted by density gradient centrifugation and stimulated by inactivated hemolytic streptococcus, the mRNA and protein expression of GADD34, GRP78, CHOP, Bcl-2, Bcl-XL, AID, Iα-Cα, and cleaved caspase-3 were examined by fluorescent RT-PCR and Western blotting. Guanabenz treatment and siRNA interference were applied to downregulate GADD34 in tonsillar mononuclear cells from IgAN patients, and P-eIF2α expression was examined by Western Blotting. Cell apoptosis was evaluated by Annexin V FITC/PI flowcytometry, and IgA secretion in cultural supernatant was inspected by enzyme linked immunosorbent assay. Results: After stimulation, the expression of GADD34 was significantly increased in IgAN patients (P< 0.05). Cell apoptosis was mitigated and IgA secretion level was elevated (P< 0.05). To be noticed, CHOP expression had no significant difference between two groups. After guanabenz treatment and siRNA interference, a prolonged elevation of P-eIF2α expression was observed. Cell apoptosis was reinforced and IgA secretion level was decreased (P< 0.05). Conclusion: GADD34 may be a potential therapeutic target for IgAN treatment due to its effect on cell apoptosis.

Deciphering roles of protein post-translational modifications in IgA nephropathy progression and potential therapy

“…GADD34 expression was elevated in IgAN patients, which was accompanied with increased apoptosis and IgA secretion. Moreover, GADD34 regulated phosphorylation of eIF1a in TMCs (tonsillar mononuclear cells) from IgAN patients [140]. Phosphorylation of STAT1 and STAT3 was increased in IgAN patients.…”

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence

“…It mitigates apoptosis by both attenuating the overall ISR pathway and promoting the stabilization of the BCL-2 family member, myeloid cell leukemia 1 (MCL1) protein. This dual action of GADD34 contributes to enhanced cellular autophagy [79][80][81].…”

Imeglimin to the Rescue: Enhanced CHOP/GADD34/eIF2α Signaling Axis Promotes β-Cell Survival

“…However, Li et al point to a potentially new paradigm in the complex and dynamic regulation of CHOP-ER homeostasis in b-cell survival, where an increase in CHOP and GADD34 expression and dephosphorylation of eIF2a ameliorates cell death. Inactivation of the CHOP/GADD34/eIF2a negative feedback loop to maintain translational inhibition has been implicated as a protective mechanism to relieve proteostatic load under stress (15), but inversely, GADD34/eIF2a loop activation was shown to mitigate death in other models (16). This raises important questions on the duality of ER stress and the role of CHOP as a proapoptotic and prosurvival protein.…”