Research

• UBE2N is essential for maintenance of skin homeostasis and suppression of inflammation.

Lee MJ, Ben Hammouda M, Miao W, Okafor AE, Jin YJ, Sun H, Jain V, Markovtsov V, Diao Y, Gregory SG, Zhang JY.   
Journal of Investigative Dermatology 2024.

• Skin Injury Activates a Rapid TRPV1-dependent Antiviral Protein Response.
  Lei V, Handfield C, Kwock JT, Kirchner SJ, Lee MJ, Coates M, Wang K, Han Q, Wang Z, Powers JG, Wolfe S, Corcoran DL, Fanelli B, Dadlani M, Ji R, Zhang JY, MacLeod AS. 
  Journal of Investigative Dermatology 2022.

• IL-27 Derived from Macrophages Facilitates IL-15 Production and T Cell Maintenance Following Allergic Hypersensitivity Responses.
  Suwanpraid J*, Lee MJ*, Hoang P, Kwock J, Floyd LP, Smith JS, Yin Z, Atwater AR, Rajagopal S, Kedl RM, Corcoran DL, Zhang JY, MacLeod AS.
  Frontiers in Immunology 2021.

• Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.
  Toyohara T, Roudnicky F, Florido MHC, Nakano T, Yu H, Katsuki S, Lee MJ, Meissner T, Friesen M, Davidow LS, Ptaszek L, Abe T, Rubin LL, Pereira AC, Aikawa M, Cowan CA.
  Cell Stem Cell 2020.

• The Skin and Intestinal Microbiota and Their Specific Innate Immune Systems.
  Coates M, Lee MJ, Norton D, MacLeod AS.
  Frontiers in Immunology 2019.

• Differential Effects of Trimetazidine on Vascular Smooth Muscle Cell and Endothelial Cell in Response to Carotid Artery Balloon Injury in Diabetic Rats.
  Yoon JW, Cho BJ, Park HS, Kang SM, Choi SH, Jang HC, Shin H, Lee MJ, Kim YB, Park KS, Lim S. 
  The International Journal of Cardiology, 2013.

UBE2N is a ubiquitin conjugating E2 enzyme specific for K63-polyubiquitination. It regulates signal transduction and DNA repair and plays critical roles in immune system development and cancer growth. However, its role in the adult skin is unclear. We have generated several conditional knockout mouse models and found that deletion of Ube2n in the adult skin leads to severe inflammation, thickening of both the epidermis and dermis, aberrant hair growth, and increased erythema. Krt5-CreER-mediated deletion of Ube2n in basal keratinocytes is sufficient to induce these phenotypes. Lgr6-CreER-mediated Ube2n loss in limited progenitor keratinocytes, however, did not lead to inflammation suggesting that the mosaic neighboring WT basal keratinocytes can help maintain homeostasis of the skin. The Ube2n-KO epidermis exhibited increased cell proliferation and enlargement of suprabasal layers undergoing differentiation, a phenotype resembling psoriatic skin and actinic keratosis. Through single-cell RNA-sequencing analyses, we found that Ube2n-deficient skin had markedly increased infiltration of immune cells predominantly comprised of neutrophils and macrophages. Differential gene expression analysis revealed significantly decreased levels of heat shock proteins (Hspa1a and Hspa1b) that are important for protein folding and increased expression of an array of cytokine and chemokine gene signatures, with IL-1 family being most highly elevated. Further, pharmacological blockade of IRAK1/4, common mediators of TLR/IL-1 signaling pathways, alleviated inflammation of the mutant skin. Together, our data highlight a key role of Ube2n in maintaining epidermal homeostasis and suppressing immune cell infiltration and identify IRAK1/4 as potential therapeutic targets for inflammatory skin disorders.