Dataset Information

Quantitative phosphosproteomics revealed substrate diversity of AMPK in response to DNA damage and its crosstalk with histone acetylation in cell apoptosis

ABSTRACT: AMPK is a conservative energy sensor that plays roles in diverse cellular processes via direct phosphorylation on various substrates. Emerging studies have demonstrated the regulatory roles of AMPK in DNA damages, but the underlying mechesiams remains to be fully understood. Our studies provided a source to study the phosphorylation and histone acetylation underlying the regulatory network of AMPK, which might be beneficial to understand the exact role of AMPK in DNA damage response.

ORGANISM(S): Mus Musculus

SUBMITTER: Minjia Tan

PROVIDER: PXD039113 | iProX | Thu Dec 29 00:00:00 GMT 2022

REPOSITORIES: iProX

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Publications

Phosphoproteomics Reveals the AMPK Substrate Network in Response to DNA Damage and Histone Acetylation.

Jiang Yuejing Y Cong Xiaoji X Jiang Shangwen S Dong Ying Y Zhao Lei L Zang Yi Y Tan Minjia M Li Jia J

Genomics, proteomics & bioinformatics 20210217 4

AMP-activated protein kinase (AMPK) is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates. Emerging studies have demonstrated the regulatory roles of AMPK in DNA repair, but the underlying mechanisms remain to be fully understood. Herein, using mass spectrometry-based proteomic technologies, we systematically investigate the regulatory network of AMPK in DNA damage response (DDR). Our system-wide phosphoproteome study uncovers a vari ...[more]

PMID: 33607295

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Project description:Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TME) and resistance to immunotherapy. The mechanisms underpin the establishment and maintenance of a cold TME in LKB1 mutant LUAD remain poorly understood and the identification of downstream effectors is critical to inform therapeutic strategies to invigorate antitumor immunity. In this study, we investigated the association between inactivation of AMPK, one of the downstream substrates of LKB1, and immune evasion in human LUAD as well as the causal role of AMPK on TME in genetically engineered mouse model (GEMM) of LUAD. Experimental Design: We modeled AMPK inactivation in vivo using GEMM by deleting both AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in KrasG12D-driven LUAD (KAA). Furthermore, we investigated the impact of AMPK inactivation on immune cell infiltration and global gene-expression programs of murine LUAD. Gene expression signature from AMPK-deficient murine LUAD was further compared to that of Lkb1 deficient murineLUAD as well as human LUAD with either LKB1 mutation or attenuated AMPK phosphorylation. Results: Inactivation of both AMPKα1 and AMPKα2 accelerates KrasG12D-driven LUAD. AMPK-deficient tumors are characterized with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with compromised immune microenvironment, which resembles LKB1-deficient murine and human LUAD (KL) as well as LKB1-wildtype LUAD with reduced AMPK phosphorylation. Attenuation of the MHC Class 1 component ß2 microglobulin (ß2M) was identified as a shared feature in KL and KAA murine LUAD as well as in human LUAD with either LKB1 mutations or reduced AMPK phosphorylation. Furthermore, reactivation of AMPK by expression of constitutive active form of AMPKα1 leads to restoration of ß2M level in LKB1 mutant LUAD cells. Conclusions: The results identify attenuation of the LKB1 substrate AMPK as an important mechanism for decreased MHC Class 1 expression and immune evasion in LKB1 mutant LUAD. Translational relevance: LKB1 loss-of-function mutations rank as the third most common genetic alterations found in lung adenocarcinoma and associated with immune evasion. In the current study, on the basis of GEMM of LUAD we established the causal relationship between inactivation of the LKB1 substrate AMPK and immune evasion. Furthermore we find that the status of AMPK phosphorylation is more sensitive than LKB1 mutation in predicting impaired tumor immune microenvironment and likely also for the resistance to immunotherapy. The results also suggest that restoration of AMPK activity could increase the number of patients benefiting from immunotherapy.

Dataset Information

Quantitative phosphosproteomics revealed substrate diversity of AMPK in response to DNA damage and its crosstalk with histone acetylation in cell apoptosis

Publications

Phosphoproteomics Reveals the AMPK Substrate Network in Response to DNA Damage and Histone Acetylation.

Similar Datasets

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