title: mTORC2-PKBα/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in psoriasis.
abstract: The connection between infections and acute guttate psoriasis (AGP) outbreaks/chronic plaque psoriasis (CPP) exacerbation has been known for years. Impaired function of FOXP3+Tregs in psoriasis has been identified. However, the mechanisms behind these two observations have not been fully interpreted. In the present study, we provide evidence to support chemokine CCL3 as one of the vital links between infections and FOXP3 stability in the psoriatic microenvironment. We found that serum CCL3, strongly induced by microorganism infections including streptococcus, was closely correlated with FOXP3 levels in CD4+CD25+T cells of patients with psoriasis. CCL3 manipulated FOXP3 stability in a concentration-dependent bidirectional manner. High-concentration CCL3 decreased FOXP3 stability by promoting FOXP3's degradation through K48-linkage ubiquitination. This degradation was mainly dependent on upregulation of Serine 473 phosphorylation of the PKBα/Akt1 isoform, and almost independent of mTORC1 (mammalian target of rapamycin complex 1) activity. On the other hand, low-concentration CCL3 could enhance FOXP3 stability by the maintenance of the PKC pathway and the restriction of the PKB/Akt pathway. We further demonstrated that enhancing FOXP3 stability by low-concentration CCL3 attributed, at least partly, to the prevention of cytoplasmic Sin1, a vital component of mTORC2, nuclear translocation. Our results suggest vital roles for CCL3-mTORC2-isoform PKB/Akt1 S473 phosphorylation axis in FOXP3+Tregs and the development of psoriasis.
authors.affiliation: Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Jinjin
authors.initials: J
authors.lastname: Wu
authors.forename: Eric
authors.initials: E
authors.lastname: Pier
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002461:Cell Line, Transformed; D054405:Chemokine CCL3 / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000276:immunology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C515429:CCL3 protein, human; D015704:CD4 Antigens; D054405:Chemokine CCL3; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C493277:MAPKAP1 protein, human; D046912:Multiprotein Complexes; D012694:Serine; C494918:AKT1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex