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ABHD1/12‐mediated TEADs depalmitoylation regulates Hippo pathway transcriptional output
Author(s) -
Tao Zhipeng,
Sun Yang,
Chen Baoen,
Guarino Carla,
Erb Hannah,
Mao Junhao,
Wu Xu
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00243
Subject(s) - hippo signaling pathway , microbiology and biotechnology , gene silencing , biology , transcription factor , palmitoylation , transcriptional regulation , gene knockdown , transcription (linguistics) , cell growth , signal transduction , cell culture , gene , enzyme , biochemistry , genetics , linguistics , philosophy , cysteine
TEAD domain (TEAD) transcription factors bind with the transcription co‐activator YAP/TAZ and regulate the transcriptional output of Hippo pathway, thus controlling organ size and tumorigenesis. Our lab previously identified that TEADs possessed intrinsic palmitoylating enzyme‐like activities and underwent autopalmitoylation, which was required for TEADs’ binding to YAP/TAZ and related to transcriptional output of Hippo pathway. Here we showed that endogenous TEADs underwent dynamic autopalmitoylation with rapid turnover rate (half‐life of TEAD1 was about 2 hours; half‐life of TEAD4 was about 2.5 hours). We found that depalmitoylation of TEAD is regulated by alpha/beta hydrolase domain proteins (ABHD1/12). This dynamic process is tightly governed by cell density, ABHD1 and ABHD12. We found that TEADs palmitoylation levels were negatively correlated with cell density and positively correlated with transcriptional activities of YAP/TAZ. Furthermore, ABHD1/12 decreased TEADs autopalmitoylation levels in a cell density dependent manner. Overexpression of ABHD1 or ABHD12 significantly promoted the turnover of TEADs palmitoylation. While silencing of ABHD1 or ABHD12 with shRNAs or treatment with ABHD12 specific inhibitor DO264 significantly increased TEADs autopalmitoylation in concomitant with increased transcriptional activities of YAP/TAZ. Immunoprecipitation and immunofluorescent staining revealed the direct binding of TEADs with ABHD1 and ABHD12. Interestingly, the inhibitory effects of ABHD1 and ABHD12 on TEADs autopalmitoylation suppressed the output of Hippo pathway in YAP‐dependent cancer cell lines, such as H226 mesothelioma cell line. Thus, ABHD1/12 are critical for the tight regulation of TEADs autopalmitoylation and transcriptional output of Hippo pathway. Further studies would be of interests and significance to explore the regulatory role of ABHD1/12‐TEADs axis ex vivo and in vivo , which will provide reference for the treatment of cancers with ABHD1/12‐TEADs malfunction and designing of drugs.