OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• OTULIN (OTU deubiquitinase with linear chain specificity) regulates ubiquitin chains.
• Dysregulation of OTULIN is implicated in inflammatory conditions.

Purpose of the Study:

• To investigate the role of OTULIN in keratinocytes for skin inflammation and tumorigenesis.
• To identify the molecular mechanisms driving OTULIN-deficiency-induced skin pathology.

Main Methods:

• Conditional knockout mouse models for Otulin ablation in keratinocytes.
• Genetic manipulation of key signaling pathways (TNFR1, RIPK1, FADD, MLKL).
• Single-cell RNA-sequencing (scRNA-seq) of lesional and non-lesional skin.
• Cytokine inhibition studies (Type-1 interferon, IL-1β).

Main Results:

• Keratinocyte-specific Otulin ablation causes inflammatory skin lesions and verrucous carcinomas.
• Genetic inhibition of RIPK1/FADD/MLKL-mediated necroptosis or TNFR1 signaling rescues the phenotype.
• scRNA-seq revealed altered epidermal stem cell identity and inflammatory signatures (Type-1 IFN, IL-1β) in OTULIN-deficient keratinocytes.
• Inhibition of these cytokines partially ameliorated skin inflammation.

Conclusions:

• Keratinocyte cell death is the primary driver of inflammation and tumorigenesis in OTULIN-deficient skin.
• OTULIN is crucial for maintaining skin immune homeostasis and preventing autoinflammatory conditions.
• Targeting specific cell death pathways or inflammatory cytokines may offer therapeutic strategies for OTULIN-related skin disorders.