RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy
Authors: Kwang Hong Tay
Chen Chen Jiang
Xu Guang Yan
Xu Dong Zhang
Yi Lun Liu
Lei Jin
Su Tang Guo
Hsin-Yi Tseng
Chun Ying Li
Qi Luan
Fritz Lai
Xiao Ying Liu
Journal: Autophagy (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATF6, activating transcription factor 6; Baf A1, bafilomycin A1; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2: β
Affiliations: School of Biomedical Sciences and Pharmacy; University of Newcastle; NSW, Australia, Department of Dermatology; Xijing Hospital; Fourth Military Medical University; Xi'an; China, School of Medicine and Public Health; University of Newcastle; NSW, Australia

Abstract:  Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM- or TG-induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM- or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM- or TG-induced ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIPK1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress. 

Retracted: No

PubPeer comments:
 Figure 2C MM200 TG treatment RIPK1shRNA1 and 2: part of the image look the same with 90u00b0 rotation , 
 Dear Psammomoya Many thanks for identifying the similarities between these two figures, which we, as senior authors, apparently ignored inadvertently. We now realize that these two figures were actually from the same one with inappropriate rotation. We have initiated internal investigations and will post you the outcome as soon as possible. Hsin-Yi Tseng and Xu Dong Zhang , 
 Dear Psammomoya We have contacted the researcher who did the experiments shown in Figure 2C. It appeared that the images of MM200 cells with RIPK1 knocked down using two shRNAs were inadvertently messed up during figure preparation. The researcher used the image generated by RIPK1 shRNA1 twice, while leaving the image from RIPK1 shRNA2 unused. Please see uploaded original photographs for clarification. We are going to contact the journal for a correction of this mistake. We do appreciate your identification of the mistake and the opportunity for us to realize and correct it. Regards Hsin-Yi Tseng and Xu Dong Zhang ![file] , 
 Can the authors please give an update on the status of the correction? Here is an illustration of Figure 2C analyzed in ImageTwin: ![file] And maybe the authors could also look at figure 3C. The first and the third column panels appear to overlap, with a 90 degrees rotation. Shown with cyan boxes. ![file] How certain are the authors that we can trust the other results? , 
 #4 Dear Elisabeth, Thank you for your comments. We have previously reached out to the journal for the correction of Figure 2C and the corrigendum has been published (PMID: 32228212, DOI: 10.1080 15548627.2020.1744941). In response to your second comment, we have contacted the researcher who organised the images shown in Figure 3C and will respond to this as soon as possible. Kind regards, Hsin-Yi Tseng and Xu Dong Zhang , 
 Dear Elisabeth, Thank you for your patience in this matter. We have contacted the researcher who prepared Figure 3C. Due to the massive number of images being processed, the person has mistakenly reused the same image twice in the same figure. Please see the original images attached below. We will contact the journal as soon as possible to have this corrected. We do appreciate your comments and will be more vigilant with our figure preparation in our future publications. Kind regards, Xu Dong Zhang and Hsin-Yi Tseng ![file] ![file] ,