AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner

Weimin Xu; Zhebin Hua; Yaosheng Wang; Wenbo Tang; Weijun Ou; Fangyuan Liu; Yiqing Yang; Wenjun Ding; Zhongchuan Wang; Long Cui; Wensong Ge; Yubei Gu; Xiaolei Wang; YingWei Chen; Chen-Ying Liu; Peng Du

doi:10.1038/s41418-024-01275-9

AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner

Cell Death Differ. 2024 Feb 29. doi: 10.1038/s41418-024-01275-9. Online ahead of print.

Authors

Weimin Xu^#^{1

2}, Zhebin Hua^#^{1

2}, Yaosheng Wang^#^{1

2}, Wenbo Tang^{1

2}, Weijun Ou^{1

2}, Fangyuan Liu^{1

2}, Yiqing Yang^{1

2}, Wenjun Ding^{1

2}, Zhongchuan Wang^{1

2}, Long Cui^{1

2}, Wensong Ge³, Yubei Gu⁴, Xiaolei Wang⁵, YingWei Chen⁶, Chen-Ying Liu^{7

8}, Peng Du^{9

10}

Affiliations

¹ Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China.
² Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
³ Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China.
⁴ Department of Gastroenterology, Rui Jin Hospital, affiliate to Shanghai Jiao Tong University, school of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China.
⁵ Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
⁶ Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China. chenyingwei@xinhuamed.com.cn.
⁷ Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.
⁸ Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. liuchenying@xinhuamed.com.cn.
⁹ Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China. dupeng@xinhuamed.com.cn.
¹⁰ Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China. dupeng@xinhuamed.com.cn.

^# Contributed equally.

PMID: 38424148
DOI: 10.1038/s41418-024-01275-9

Abstract

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.

Abstract

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