{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Filaggrin‐2 (FLG2) is a member of the S100 fused‐type protein family that shares structural and functional similarities with filaggrin, and it plays several key roles in epidermal differentiation and barrier function. FLG2 is expressed in keratinocytes—predominantly in the upper granular cells—where its transcription parallels that of filaggrin, suggesting coordinated involvement in terminal differentiation and cornification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Once expressed, FLG2 is proteolytically processed to generate products that contribute to the pool of natural moisturizing factors required for skin hydration. In this context, FLG2 degradation is tightly regulated by enzymes such as calpain 1—with deimination accelerating its proteolysis—which underscores its dynamic processing during cornification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to providing precursors for moisturizing factors, FLG2 supports intercellular adhesion within the cornified cell layers by modulating the expression of key adhesion molecules (e.g., corneodesmosin). Loss‐of‐function mutations in FLG2 have been associated with clinical phenotypes such as persistent atopic dermatitis and peeling skin syndromes, highlighting its essential role in maintaining barrier integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic variation in FLG2 has been linked to differences in disease course in atopic dermatitis; for instance, certain uncommon alleles are associated with improved remission outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its structural role, FLG2 also appears to have a direct antimicrobial function. C‐terminal fragments derived from FLG2 display potent activity against bacteria such as Pseudomonas, acting by inducing membrane blebbing and interfering with bacterial replication."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, the N‐terminal domain of FLG2 has been found to interact with and promote the autoactivation of SASPase, a protease involved in filaggrin processing. This interaction suggests that FLG2 not only directly contributes to the formation of natural moisturizing factors and barrier integrity but also modulates upstream proteolytic pathways that are critical for proper skin maturation and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhihong Wu, Britta Hansmann, Ulf Meyer-Hoffert, et al. 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