Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

Abstract

Endoplasmic reticulum (ER) stress is a mechanism that allows the protection of normal cellular functions in response to both internal perturbations, such as accumulation of unfolded proteins, and external perturbations, for example redox stress, UVB irradiation, and infection. A hallmark of ER stress is the accumulation of misfolded and unfolded proteins. Physiological levels of ER stress trigger the unfolded protein response (UPR) that is required to restore normal ER functions. However, the UPR can also initiate a cell death program/apoptosis pathway in response to excessive or persistent ER stress. Recently, it has become evident that chronic ER stress occurs in several diseases, including skin diseases such as Darier's disease, rosacea, vitiligo and melanoma; furthermore, it is suggested that ER stress is directly involved in the pathogenesis of these disorders. Here, we review the role of ER stress in skin function, and discuss its significance in skin diseases.

Keywords: endoplasmic reticulum stress; skin disease; skin function; unfolded protein response.

Fig. 1.. The three branches of the unfolded protein response (UPR).

In unstressed conditions, stress sensor proteins activating transcription factor (ATF) 6, inositol-requiring enzyme (IRE1) α, and RNA-dependent protein kinase-like ER-resident kinase (PERK), representing the three branches of the UPR, are associated with the folding chaperone glucose regulated protein/binding immunoglobulin protein (GRP78/BiP) in the ER. Accumulation of unfolded/misfolded proteins within the ER lumen causes GRP78/BiP disassociation from these three sensor proteins, leading to UPR activation. Each pathway uses a different mechanism of signal transduction. Activated IRE1α mediates unconventional splicing of X-box binding protein (XBP) 1 to produce spliced, active isoform of XBP1. IRE1α recruits TNF receptor associated factor (TRAF) 2 to activate the downstream signal mediators, NF-κB/JNK. IRE1α-mediated activations of XBP1 and TRAF2/NF-κB/JNK regulate UPR target genes associated with lipid metabolism, immune, inflammatory response, and differentiation, as well as structural/ functional expansion of ER and ER-associated protein degradation (ERAD). In addition, IRE1α can reduce the ER protein folding load by the IRE1-dependent decay of mRNA (RIDD) causing degradation of ER membrane-bound mRNAs. Activated PERK recruits and phosphorylates eukaryotic initiation factor (eIF2) α reduce global protein synthesis and thereby reduce protein folding load in ER-stressed cells. Paradoxically, however, PERK/eIF2α-translation of ATF4 increases certain UPR gene transcriptions, including CCAAT-enhancer-binding protein homologous protein (CHOP). Lastly, activated ATF6 is exported to the Golgi apparatus where it is cleaved by the Golgi-resident proteases SP1 and SP2 to produce the functional fragment of ATF6. The functional ATF6 is then translocated to the nucleus where it transactivates UPR genes associated with ER homeostasis.

Fig. 2.. Role of ER stress in Darier’s disease.

In Darier’s disease, mutations in the ATP2A2 gene, which encodes the SERCA2, cause impaired transport of calcium from cytosol to ER, thereby leading to chronic ER stress in keratinocytes. ER calcium is an important regulator of the reorganization of adherens junctions and desmosomes. Defective ER calcium homeostasis in keratinocytes of Darier’s disease may contribute to abnormal cell-to-cell adhesion via defective reorganization of junctional components, causing acantholysis. In addition, chronic ER stress triggers the disproportionate activation of the apoptotic component of the UPR. PERK-dependent apoptotic signaling can contribute to the non-physiologic and premature keratinocyte apoptosis which can be observed as dyskeratotic keratinocytes (“corp ronds”) in Darier’s disease. Taken together, ER stress is implicated in the pathogenesis of Darier’s disease characterized histologically by acantholytic dyskeratosis.

Fig. 3.. Role of ER stress in Rosacea.

Rosacea is a chronic inflammatory condition, in which both innate and adaptive immune responses are activated by multiple environmental factors. Many triggering factors of rosacea can induce ER stress and UPR signaling pathways in keratinocytes. ATF4-mediated signaling induces TLR2 expression and TLR2-mediated innate immune responses. Subsequently, TLR2 increases KLK5 expression in keratinocytes. ER stress can also induce cathelicidin production by S1P signaling pathway in keratinocytes. Excess cathelicidin and their proteolytic processing by KLK5 play a central role in the innate immune activation of rosacea.