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FBXW7 modulates cellular stress response and metastatic potential through ?HSF1 post-translational modification.

ABSTRACT: ?Heat-shock factor 1 (?HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate ?HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase ?FBXW7? interacts with ?HSF1 through a conserved motif phosphorylated by ?GSK3? and ?ERK1. ?FBXW7? ubiquitylates ?HSF1 and loss of ?FBXW7? results in impaired degradation of nuclear ?HSF1 and defective heat-shock response attenuation. ?FBXW7? is either mutated or transcriptionally downregulated in melanoma and ?HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. ?FBXW7? deficiency and subsequent ?HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the ?HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

SUBMITTER: Kourtis N

PROVIDER: S-EPMC4401662 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

Kourtis Nikos N Moubarak Rana S RS Aranda-Orgilles Beatriz B Lui Kevin K Aydin Iraz T IT Trimarchi Thomas T Darvishian Farbod F Salvaggio Christine C Zhong Judy J Bhatt Kamala K Chen Emily I EI Celebi Julide T JT Lazaris Charalampos C Tsirigos Aristotelis A Osman Iman I Hernando Eva E Aifantis Iannis I

Nature cell biology 20150301 3

Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FB ...[more]

PMID: 25720964

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Project description:BackgroundThe chronic airway inflammation in severe eosinophilic asthma (SEA) suggests potential autoimmune aetiology with unidentified autoantibodies analogous to myeloperoxidase (MPO) in ANCA-positive EGPA (eosinophilic granulomatosis with polyangiitis). Previous research has shown that oxidative post-translational modification (oxPTM) of proteins is an important mechanism by which autoantibody responses may escape immune tolerance. Autoantibodies to oxPTM autoantigens in SEA have not previously been studied.MethodsPatients with EGPA and SEA were recruited as well as healthy control participants. Autoantigen agnostic approach: Participant serum was incubated with slides of unstimulated and PMA-stimulated neutrophils and eosinophils, and autoantibodies to granulocytes were identified by immunofluorescence with anti-human IgG FITC antibody. Target autoantigen approach: Candidate proteins were identified from previous literature and FANTOM5 gene set analysis for eosinophil expressed proteins. Serum IgG autoantibodies to these proteins, in native and oxPTM form, were detected by indirect ELISA.ResultsImmunofluorescence studies showed that serum from patients with known ANCA stained for IgG against neutrophils as expected. In addition, serum from 9 of 17 tested SEA patients stained for IgG to PMA-stimulated neutrophils undergoing NETosis. Immunofluorescent staining of eosinophil slides was evident with serum from all participants (healthy and with eosinophilic disease) with diffuse cytoplasmic staining except for one SEA individual in whom subtle nuclear staining was evident. FANTOM5 gene set analysis identified TREM1 (triggering receptor expressed on myeloid cells 1) and IL-1 receptor 2 (IL1R2) as eosinophil-specific targets to test for autoantibody responses in addition to MPO, eosinophil peroxidase (EPX), and Collagen-V identified from previous literature. Indirect ELISAs found high concentrations of serum autoantibodies to Collagen-V, MPO, and TREM1 in a higher proportion of SEA patients than healthy controls. High concentrations of serum autoantibodies to EPX were evident in serum from both healthy and SEA participants. The proportion of patients with positive autoantibody ELISAs was not increased when examining oxPTM compared to native proteins.DiscussionAlthough none of the target proteins studied showed high sensitivity for SEA, the high proportion of patients positive for at least one serum autoantibody shows the potential of more research on autoantibody serology to improve diagnostic testing for severe asthma.Clinical trial registrationClinicalTrials.gov, identifier, NCT04671446.

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FBXW7 modulates cellular stress response and metastatic potential through ?HSF1 post-translational modification.

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

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FBXW7 modulates cellular stress response and metastatic potential through ?HSF1 post-translational modification.

Publications

FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

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OmicsDI is part of the ELIXIR infrastructure

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.