RIPK1 regulates the survival of human melanocytes upon endoplasmic reticulum stress

Abstract

Vitiligo is a common congenital or acquired disfiguring skin disorder. At present, endoplasmic reticulum (ER) stress has been identified to serve a critical role in the pathogenesis of vitiligo. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a protein serine/threonine kinase. The specific molecular mechanism of RIPK1 in human melanocytes upon ER stress remains to be determined. In the present study, RIPK1 was significantly downregulated in tunicamycin (TM)-induced ER stressed-human melanocytes. Subsequently, to explore the role of RIPK1 in ER stress-induced human melanocytes, human melanocytes were transfected with control or RIPK1 plasmids for 24 h and then treated with 3 µM TM for 48 h. Reverse transcription-quantitative PCR and western blot analysis indicated that the expression levels of protein kinase R-like endoplasmic reticulum kinase, eukaryotic translation initiation factor 2 subunit 1 and CCAAT-enhancer-binding protein homologous protein were significantly increased in the TM-treated group compared with the controls. In addition, the effect of high RIPK1 expression on ER stress-induced human melanocyte survival was studied. The present results indicated that TM inhibited cell viability and promoted apoptosis in human primary epidermal melanocytes. Western blot analysis demonstrated that the expression of Bax and caspase-3 was upregulated and the expression of Bcl-2 was downregulated in TM-treated human melanocytes. The effects of TM on human melanocytes were reversed by RIPK1 overexpression. Therefore, RIPK1 overexpression may have an effect on the PI3K/AKT/mTOR signaling pathway in human melanocytes under ER stress. The results of the current study demonstrated that RIPK1 could protect human melanocytes from cell damage induced by ER stress by regulating the PI3K/AKT/mTOR and ER stress signaling pathways, thereby serving a protective role in the occurrence and development of vitiligo.

p38MAPK guards the integrity of endosomal compartments through regulating necrotic death

“…S6 online), which undoubtedly leads to a dramatic phenotypic changes in TM-treated cells compared to mock-treated controls, one of the effects of TM conditioning we found was a reduction in the amounts of intracellular RIPK1, which correlated with sensitizing cells to NP-induced necrotic death. Although TM treatment did not appear to reduce the amount of intracellular RIPK1 in MEF cells 54 , recent studies using primary human melanocytes 55 and primary human melanocyte HEMn-MP cells 56 showed that TM treatment leads to a reduction of intracellular RIPK1, similar to finding in our system, when primary mouse BMDM were cultured on serumtreated glass slides. We further found that a necroptosis inhibitor GSK872, which was previously determined to function by blocking catalytic activity of RIPK3, was able to stabilize amounts of RIPK1 in TM-treated cells and protect cells from NP-induced necrotic death.…”

Height and Risk of Vitiligo: A Nationwide Cohort Study

“…Genetic factors contribute strongly to adult height, and certain genes linked with height [22] are involved in vitiligo-regulatory pathways. These include JNK (jun amino terminal kinase), PI3K (phosphatidylinositol 3 kinase), JAK1 (Janus kinase 1), CREB (cyclic AMP responsive element-binding) protein, ERK (extracellular signal-regulated kinase), and mTOR (mammalian target of rapamycin) [45][46][47][48]. JNK is involved in growth plate development and chondrocyte differentiation [49] and suppresses melanogenesis by interfering with CREB-regulated transcription coactivator 3-dependent microphthalmia-associated transcription factor (MITF) activation [50].…”

Endoplasmic Reticulum Dysfunction: An Emerging Mechanism of Vitiligo Pathogenesis

“…In addition to XBP1, it was reported that receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein serine/threonine kinase, could protect melanocytes from cell damage caused by ER stress by regulating the PI3K/AKT/mTOR and ER stress signaling pathways. 58 Therefore, more and more researchers have demonstrated the ER morphological and genetic abnormalities of melanocytes in vitiligo. Interestingly, ERS could not only induce melanocyte damage but also was reported to be associated with melanogenesis.…”