Bacterial type III effector protein HopQ inhibits melanoma motility through autophagic degradation of vimentin

Seung-Ho Park,Young-Jun Park,Sung-Jin Yoon,Moo-Seung Lee,Seon-Jin Lee,Mi-Young Son,Choong-Min Ryu,Jun-Seob Kim,Sang-Hyun Lee,Jiyun Yoo,Song Choi,Jeong-Ki Min

doi:10.1038/s41419-020-2427-y

Abstract

Malignant melanoma is a fatal disease that rapidly spreads to the whole body. Treatments have limited efficiency owing to drug resistance and various side effects. Pseudomonas syringae pv. tomato (Pto) is a model bacterial pathogen capable of systemic infection in plants. Pto injects the effector protein HopQ into the plant cytosol via a type III secretion machinery and suppresses the host immunity. Intriguingly, host plant proteins regulated by HopQ are conserved even in humans and conferred in tumor metastasis. Nevertheless, the potential for HopQ to regulate human cancer metastasis was unknown. In this study, we addressed the suitability of HopQ as a possible drug against melanoma metastasis. In melanoma cells, overexpressed HopQ is phosphorylated and bound to 14-3-3 through its N-terminal domain, resulting in stronger interaction between HopQ and vimentin. The binding of HopQ to vimentin allowed for degradation of vimentin via p62-dependent selective autophagy. Attenuation of vimentin expression by HopQ inhibited melanoma motility and in vivo metastasis. These findings demonstrated that HopQ directly degraded vimentin in melanoma cells and could be applied to an inhibitor of melanoma metastasis.

Highlights

Melanoma is a tumor formed by pigment-producing cells called melanocytes, with the highest prevalence among all skin cancers
We demonstrated that the HopQ from a plant pathogen pv. tomato (Pto) interacts with [-3] in melanoma cells and regulates vimentin stability, inhibiting metastasis of melanoma cells
HopQ binds to vimentin and inhibits its stability In an attempt to identify possible signaling pathways regulated by the HopQ/14-3-3 interaction, we examined the expression of [-3] signaling-related proteins involved in cell motility

Summary

Introduction

Melanoma is a tumor formed by pigment-producing cells called melanocytes, with the highest prevalence among all skin cancers. Depending on the origin of the primary tumor, melanoma can be classified as follows: cutaneous, acral, mucosal, and uveal melanoma. Cutaneous melanoma is the most common type of melanoma and is the leading cause of 75% of skin cancerrelated deaths[1]. Cutaneous melanomas are stimulated by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, owing to BRAF or NRAS mutations, promoting cell proliferation, differentiation, and growth[2]. Immunosuppression via surface proteins expressed in melanoma cells, such as programmed cell death protein 1 ligand 1 (PDL1) and PDL2, has a vital role in the development and progression of melanomas[3]. BRAF inhibitors can cause serious side effects such as squamous cell carcinoma[6].

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