ABSTRACT
Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10-6) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.
Subject(s)
Keratinocytes , Pityriasis Rubra Pilaris , Skin , Adult , Animals , Female , Humans , Male , Mice , Middle Aged , Young Adult , Case-Control Studies , Homeostasis , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Keratins/metabolism , Keratins/genetics , Loss of Function Mutation , Mice, Knockout , NF-kappa B/metabolism , Pityriasis Rubra Pilaris/genetics , Pityriasis Rubra Pilaris/immunology , Pityriasis Rubra Pilaris/pathology , Pityriasis Rubra Pilaris/metabolism , Signal Transduction , Skin/pathology , Skin/immunology , Skin/metabolism , UbiquitinationABSTRACT
A highly enantioselective Mannich reaction of α-fluoroindanones with isatin-derived N-Boc-ketimines catalyzed by a quinine-derived phase-transfer catalyst was developed. A variety of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing, vicinal, tetrasubstituted stereocenters were constructed using this protocol in high yields (83-95%), with moderate to excellent enantioselectivities (66-91%) and high diastereoselectivities (up to >99:1).