Erythroid differentiation regulator 1 (Erdr1) is a proapototic factor in human keratinocytes

Abstract

Skin is constantly exposed to physical and chemical stressors. The exposure of keratinocytes to ultraviolet B (UVB) irradiation causes epidermal damage via induction of apoptosis. Erythroid differentiation regulator 1 (Erdr1) modulates growth and survival of cells under various stressful conditions, but the function of Erdr1 in human keratinocyte apoptosis has not been investigated so far. Here, we investigated the effect of Erdr1 on UVB-induced apoptosis in human keratinocytes and also examined the underlying regulatory mechanism. First, Erdr1 expression was detected in human primary keratinocytes and normal human skin tissues. Expression of Erdr1 was enhanced in human keratinocytes following UVB irradiation. Knock-down of Erdr1 led to resistance to UVB-induced apoptosis. Also, Erdr1 overexpression increased UVB-induced apoptosis and induced caspase-3 activation. Furthermore, the extracellular signal-regulated kinase (ERK) inhibitor PD98059 and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 significantly reduced Erdr1 expression following UVB irradiation. These results indicate that UVB induces Erdr1 via a MAPK-dependent mechanism. Taken together, these findings suggest that Erdr1 has a role as a proapoptotic factor in human keratinocytes and acts via ERK and p38 MAPK pathways. Therefore, Erdr1 may be a potential therapeutic target to reduce apoptosis in keratinocytes in conditions such as psoriasis and skin cancer.

ERDR1 enhances human NK cell cytotoxicity through an actin-regulated degranulation-dependent pathway

“…ERDR1 induces hemoglobin synthesis and is a stressrelated survival factor [17,18]. Recently, ERDR1 was reported to be a pro-apoptotic factor in human keratinocytes and an antimetastasis factor in mouse melanoma cells and human gastric cancer cells [19][20][21]. This study investigated whether ERDR1 has anti-cancer effects on immune cells, human primary NK cells, as well as cancer cells.…”

“…Additionally, ERDR1 inhibits gastric cancer cell migration and invasion [21]. ERDR1 is expressed in human keratinocytes and is detected in the cultured supernatants of murine erythroleukemia cells [17,19]. Although ERDR1 is regarded as a metastasis suppressor in cancer cells, its role in immune cells is still unknown.…”

“…In human keratinocytes, ERDR1 is involved in cell growth and survival and is regarded as a pro-apoptotic factor [19]. Recently, ERDR1 expression is negatively regulated by IL-18, causing anti-metastatic functions in melanoma [20].…”

Microbiota promotes systemic T-cell survival through suppression of an apoptotic factor

“…Erdr1 is a vesicleassociated secreted protein that is ubiquitously expressed (11,15). It has reported functions in keratinocytes and NK cells, although there are currently no known roles for Erdr1 in T lymphocytes (13,14). A knockout mouse model does not exist to study the role of Erdr1, and our attempts to make a whole-body knockout using Crisper/Cas9 technology revealed that loss of this gene is not tolerated in utero ( Fig.…”

“…Erdr1 was originally identified in supernatants of B-cell leukemic cells and named for its hemoglobin-inducing activity on erythroid lines, but now has implicated roles in cellular survival, NK cytotoxicity, and metastasis; however, its function within T cells remains completely unexplored (11)(12)(13)(14)(15).…”