1) Epithelial Barrier Integrity and Skin Microbiota in Kojak Mice

Atopic dermatitis (AD) is prevalent in modern society, especially in infant and child, and causes a long-term effect in life, development and learning. AD is a complex chronic inflammatory skin disorder that results from intimate interactions among genetic predisposition, host environment, skin barrier defects, and immunological factors. However, a clear genetic roadmap leading to atopic dermatitis remains to be fully explored. From a genome-wide mutagenesis screen, deficiency of ZDHHC13, a palmitoylacyl transferase, has previously been shown to be associated with skin and multitissue inflammatory phenotypes. Genetic and immunological studies revealed that this dermatitis is a keratinocyte-cell autonomous disorder, and is not caused by adaptive immunity, nor by TNF-a, nor IL-1b. To clarify the importance of palmitoylation enzyme activity and its substrates, we generated knock-in mice to destroy the enzymatic site of ZDHHC13 protein and the results suggested that knock-in mice phenocopy the knock-out mice. Further quantitative tandem mass spectra revealed that multiple pathways are regulated by ZDHHC13, including filaggrin degradation and hydrolysis pathways. On the other hand, to study how skin microbiota cross-talk with the defective barrier, we established a cleaner SPF room that can prevent skin inflammation of Kojak mice, like in Germ-free room, and currently is studying the bacterial dysbiosis. Our future goal will include identification of dysbiosis and microbiota functional composition responsible for skin inflammation. Seeking for the underlying mechanism of dysbiosis-associated skin inflammation and development of innovative therapeutics to treat human atopic dermatitis are our final goals.

1. Song IW, Li WR, Chen LY, Shen LF, Liu KM, Yen JJ, Chen YJ, Chen YJ, Kraus VB, Wu JY, Lee MT, Chen YT. Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model. PLoS One. 2014 Mar 17;9(3):e92194. doi:10.1371/journal. pone. 0092194.
 

2. Liu KM, Chen YJ, Shen LF, Haddad AN, Song IW, Chen LY, Chen YJ, Wu JY, Yen JJ, Chen YT. Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13- Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation. J Invest Dermatol. 2015 Nov;135(11):2603-10. doi: 10.1038/jid. 2015.240. 
 

3. Shen LF, Chen YJ, Liu KM, Haddad ANS, Song IW, Roan HY, Chen LY, Yen JJY, Chen YJ, Wu JY, Chen YT. Role of S-Palmitoylation by ZDHHC13 in Mitochondrial function and Metabolism in Liver. Sci Rep. 2017 May 19;7(1):2182. doi: 10.1038/s41598-017-02159-4.
 

4. Chen LY, Yang-Yen HF, Tsai CC, Thio CL, Chuang HL, Yang LT, Shen LF, Song IW, Liu KM, Huang YT, Liu FT, Chang YJ, Chen YT, Yen JJ. Protein Palmitoylation by ZDHHC13 Protects Skin against Microbial-Driven Dermatitis. J Invest Dermatol. 2017 Apr;137(4):894-904. doi: 10.1016/j.jid.2016.12.011. Epub 2016 Dec 23. 

2) CBAP acts as a novel oncoprotein in human T cell acute lymphoblastic leukemia

A relative high frequency of relapse remains a clinical enigma for cure of T-cell acute lymphoblastic leukemia (T-ALL) patients, which has recently been implicated with heterogeneous dysregulated signaling profiles. Recently, we demonstrated that GM-CSF/IL-3/IL-5 receptor common b-chain-associated protein (CBAP) is highly expressed in many human T-ALL cell lines and is required to bolster leukemia cell in vitro proliferation and in vivo leukemogenesis in xenograft mouse model. Down-regulation of CBAP markedly restrains expansion of leukemia cells and alleviates disease aggravation of leukemic mice. Transcriptomic profiling and biochemical analyses reveal that CBAP acts as a key regulator of Raf-MEK-ERK and Akt-mTORC1 signaling pathways to control leukemia cell growth. Here we further found that CBAP physically associates with Akt and TSC2 through independent domains, and serves as a scaffold protein to facilitate Akt-dependent TSC2 phosphorylation, leading to elevated Rheb-GTP loading and subsequent activation of mTORC1 signaling. Disruption of this tripartite complex through ectopic expression of N-terminal 26 residues of CBAP shows a relieve of Akt-mediated TSC2 phosphorylation, resulting in suppression of leukemia cell growth. Taken together, our findings uncover CBAP a novel oncogenic contribution to T-ALL leukemogenesis and a functional role in regulation of Akt-TSC2-mTORC1 signaling for leukemia cell proliferation, and may provide a therapeutic strategy to suppress many types of Akt-TSC2-mediated cancers.

1. Chiang YJ, Ho KC, Liao WT, Liu CS, Chen YG, Ho CL, Huang SF, Shih LY, Yang-Yen HF, Yen JJ. CBAP regulates the Rheb-GAP activity of TSC2 complexes by promoting Akt-dependent TSC2 phosphorylation and TSC1 displacement. 2017. In revision.

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