CALML5 is a ZNF750- and TINCR-induced protein that binds stratifin to regulate epidermal differentiation

Sun, Bryan K.; Boxer, Lisa D.; Ransohoff, Julia D.; Siprashvili, Zurab; Qu, Kun; Lopez-Pajares, Vanessa; Hollmig, S. Tyler; Khavari, Paul A.

doi:10.1101/gad.267708.115

Cited by 67 publications

(59 citation statements)

References 28 publications

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“…They usually became confluent on the 6th day, gradually differentiated into mature keratinocytes, and then underwent cellular senescence. As previously shown (Méhul et al, ; Hwang and Morasso, ; Sun et al, ), the expression of CLSP is likely induced by differentiation and senescence in keratinocytes. In the current study, the expression of CLSP in NHEKs was undetectable on the 6th day, started to be detected on the 9th day, and increased on the 13th days (Figure A).…”

Section: Resultssupporting

confidence: 61%

“…Some findings regarding the function of CLSP in skin tissues have been provided. The expression of CLSP is induced by keratinocyte differentiation (Méhul et al, ), and CLSP plays an essential role in inducing the differentiation of keratinocytes, co‐operatively with its binding partner 14‐3‐3σ (Sun et al, ). Scarf, a mouse orthologue of CLSP, may play a critical role in the process of restoring the murine epidermal Ca 2+ gradient during wound healing and epidermal barrier formation (Hwang et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

Yusuke

Miyachi

Nawa

et al. 2019

Cell Biology International

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Calmodulin‐like skin protein (CLSP) is a secreted peptide that is produced by skin keratinocytes and some related epithelial cells. It has previously been shown that CLSP is recruited via the bloodstream into the central nervous system where it likely exerts a neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activating intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP shows a protective effect in the skin tissues. In the current study, using primary keratinocytes treated with hydrogen peroxide (H2O2) or exposed to ultraviolet (UV) irradiation as senescence models of keratinocytes, we addressed whether CLSP affects senescence in skin keratinocytes. We found that CLSP expression was upregulated by H2O2 or UV in keratinocytes. Furthermore, co‐incubation with recombinant CLSP reduced the increase in senescence‐associated β‐galactosidase‐positivity in keratinocytes that were induced by H2O2 or UV. These results suggest that CLSP may function as a senescence‐suppressing factor in keratinocytes.

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Section: Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

Yusuke

Miyachi

Nawa

et al. 2019

Cell Biology International

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“…These changes have also been observed in subjects with atopic dermatitis and psoriasis . Calmodulin‐like proteins interact with stratifin and control some of the late differentiation genes . These proteins may be increased to try and improve keratinocyte differentiation, but clearly, this is not occurring on the cheek.…”

Section: Discussionmentioning

confidence: 94%

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

Voegeli

Monneuse²,

Schoop

et al. 2017

Intern J of Cosmetic Sci

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BACKGROUND:The effect of photodamage on facial stratum corneum (SC) is still poorly understood. OBJECTIVE: To describe the SC proteome from tape strippings of Caucasian SC from photoexposed cheek and photoprotected postauricular (PA) site, a global analysis of photodamage on the skin will be developed leading to a better understanding of keratinocyte signalling pathways and identification of new molecular targets for the treatment of photoaged skin. METHODS: Female Caucasian subjects had nine consecutive tape strippings taken from their cheeks and PA site. Proteins were extracted and the trypsin-digested peptides were analysed by nanochromatography coupled to a high-resolution mass spectrometer. Data-dependent acquisition allowed protein identification that was processed by Paragon algorithm of Protein Pilot software. RESULTS: Changes in the levels of epidermal differentiation proteins were apparent indicating poor epidermal differentiation and SC maturation (keratins, cornified envelope (CE) proteins) on photoexposed cheeks. Differences in protease-anti-protease balance were observed for corneodesmolysis (favouring desquamation) and filaggrinolysis (favouring reduced filaggrin processing). 12R-LOX, a CE maturation enzyme, was reduced in photodamaged skin but not transglutaminases. Changes in signal keratinocyte transduction pathway markers were demonstrated especially by reduced levels of downstream signalling markers such as calreticulin (unfolded protein response; UPR) and increased level of stratifin (target of rapamycin; mTOR). Evidence for impaired proteostasis was apparent by reduced levels of a key proteasomal subunit (subunit beta type-6). Finally, key antioxidant proteins were upregulated except catalase. CONCLUSION: Clear examples of poor keratinocyte differentiation and associated metabolic and signalling pathways together with reduced SC maturation were identified in photodamaged facial SC. Corneocyte immaturity was evident with changes in CE proteins. Particularly, the reduction in 12R-LOX is a novel finding in photodamaged skin and supports the lack of SC maturation. Moreover, filaggrinolysis was reduced, whereas corneodesmolysis was enhanced. From our results, we propose that there is a poor crosstalk between the keratinocyte endoplasmic reticulum UPR, proteasome network and autophagy machinery that possibly leads to impaired keratinocyte proteostasis. Superimposed on these aberrations is an apparently enhanced mTOR pathway that also contributes to reduced SC formation and maturation. Our results clearly indicate a corneocyte scaffold disorder in photodamaged cheek SC.R esum e CONTEXTE: Les effets des dommages dus a l'exposition a la lumiere sur le stratum corneum (SC) sont encore mal compris. OBJECTIFS: D ecrire le prot eome du SC issu de pr el evements par bandes adh esives provenant de la joue, expos ee a la lumi ere, et de la r egion post-auriculaire, prot eg ee de la lumi ere, de sujets caucasiens.A cette fin, une analyse globale des dommages cutan es dus a l'exposition a la lumi er...

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“…This analysis revealed 3225 DE genes ( P < 0.05, fold change > 2, RPKM > 1; table S3). The majority (77%) of the genes modified by SPINK7 silencing were also modulated during epithelial cell differentiation, including a regulator of terminal epidermal differentiation, calmodulin-like 5 (CALML5) ( 19 ), and the cornified envelope components expressed by differentiated keratinocytes, such as FLG and LOR (fig. S3C shows the top dysregulated genes that overlap between differentiation and SPINK7 silencing).…”

Section: Resultsmentioning

confidence: 99%

The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses

et al. 2018

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Loss of barrier integrity has an important role in eliciting type 2 immune responses, yet the molecular events that initiate and connect this with allergic inflammation remain unclear. We reveal an endogenous, homeostatic mechanism that controls barrier function and inflammatory responses in esophageal allergic inflammation. We show that a serine protease inhibitor, SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium and that SPINK7 depletion occurs in a human allergic, esophageal condition termed eosinophilic esophagitis. Experimental manipulation strategies reducing SPINK7 in an esophageal epithelial progenitor cell line and primary esophageal epithelial cells were sufficient to induce barrier dysfunction and transcriptional changes characterized by loss of cellular differentiation and altered gene expression known to stimulate allergic responses (for example, FLG and SPINK5). Epithelial silencing of SPINK7 promoted production of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP). Loss of SPINK7 increased the activity of urokinase plasminogen-type activator (uPA), which in turn had the capacity to promote uPA receptor-dependent eosinophil activation. Treatment of epithelial cells with the broad-spectrum antiserine protease, α1 antitrypsin, reversed the pathologic features associated with SPINK7 silencing. The relevance of this pathway in vivo was supported by finding genetic epistasis between variants in TSLP and the uPA-encoding gene, PLAU. We propose that the endogenous balance between SPINK7 and its target proteases is a key checkpoint in regulating mucosal differentiation, barrier function, and inflammatory responses and that protein replacement with antiproteases may be therapeutic for select allergic diseases.

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CALML5 is a ZNF750- and TINCR-induced protein that binds stratifin to regulate epidermal differentiation

Cited by 67 publications

References 28 publications

Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses

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