TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression

Tai-Mei Zhang; Li Liao; Shao-Ying Yang; Min-Ying Huang; Yin-Ling Zhang; Ling Deng; Shu-Yuan Hu; Fan Yang; Fang-Lin Zhang; Zhi-Min Shao; Da-Qiang Li

doi:10.1080/15548627.2022.2103992

TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression

Autophagy. 2023 Mar;19(3):805-821. doi: 10.1080/15548627.2022.2103992. Epub 2022 Aug 3.

Authors

Tai-Mei Zhang¹, Li Liao^{1

2

3}, Shao-Ying Yang¹, Min-Ying Huang¹, Yin-Ling Zhang^{1

2

3}, Ling Deng¹, Shu-Yuan Hu¹, Fan Yang⁴, Fang-Lin Zhang^{1

2

3}, Zhi-Min Shao^{1

2

3

4

5

6}, Da-Qiang Li^{1

2

3

4

5

6}

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai Yangpu, China.
² Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.
⁴ Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.
⁵ Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.
⁶ Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, Yangpu, China.

Abstract

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung metastasis in vivo. Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both in vitro and in vivo. Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor.Abbreviations: ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A₁; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.

Keywords: Macroautophagic degradation; proteostasis; selective autophagy receptor; transmembrane protein; triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis Regulatory Proteins / metabolism
Autophagy
Endoplasmic Reticulum-Associated Degradation
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Membrane Proteins / metabolism
Signal Transduction
Triple Negative Breast Neoplasms*
Valosin Containing Protein / metabolism

Substances

Valosin Containing Protein
Apoptosis Regulatory Proteins
Membrane Proteins
TOLLIP protein, human
Intracellular Signaling Peptides and Proteins
VCP protein, human

Grants and funding

This work is supported, in whole or in part, by the National Natural Science Foundation of China (82072918 to FLZ; 81572584, 81772805, and 82173275 to DQL) and by the National Key R&D Program of China (2017YFC0908400 and 2018YFE0201600 to DQL).