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

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 Nterminal 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.

Vimentin's side gig: Regulating cellular proteostasis in mammalian systems

“…WFA's prevention of vimentin polymerization also could result in increases in vimentin degradation which could overwhelm protein turnover systems and lead to measurable perturbations in autophagy such as what was reported. This scenario is further supported by the recent observation that vimentin can be degraded by autophagy (Park et al, 2020). Thus, it would be interesting to reexamine these findings in a vimentin KO or knock‐down (KD) cell line which may be less limited by the non‐specific activities of WFA.…”

“…WFA's prevention of vimentin polymerization also could result in increases in vimentin degradation which could overwhelm protein turnover systems and lead to measurable perturbations in autophagy such as what was reported. This scenario is further supported by the recent observation that vimentin can be degraded by autophagy (Park et al, 2020).…”

“…While there are numerous scenarios in which vimentin's activity at the aggresome could be interpreted as beneficial, there are also scenarios in which the organism sustains greater consequences from an optimally functioning vimentin‐caged aggresome such as in cancers and viral infection. Aggresomes and vimentin are widely studied chemotherapeutic targets in combination with proteasome inhibitors in cancers such as multiple myeloma, breast cancer and pancreatic cancer (Komatsu et al, 2013; Mishima et al, 2015; Nawrocki et al, 2006; Park et al, 2020). Interestingly, indirectly inhibiting aggresome function synergistically increases cytotoxicity associated with proteasome inhibition in a pancreatic cancer xenograft (Nawrocki et al, 2006).…”

Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages

“…7b ). To confirm the PM-induced changes in the metastatic ability of cancer cells, we injected B16F10 mouse melanoma cells, an established model of metastasis 42 , into mice via the tail vein, and beginning on the subsequent day, injected PM into the lungs for 3 days (Supplementary Fig. 10a ).…”

Autophagy Takes Center Stage as a Possible Cancer Hallmark

“…The cargo receptor p62/SQSTM1 is one of most extensively studied receptors and modulates selective autophagy due to its mediation in the degradation of ubiquitinated material, such as protein aggregates, mitochondria, peroxisomes, lysosomes, or intracellular bacteria (22). For example, the binding of the bacterial type III effector protein HopQ to vimentin provokes the degradation of vimentin through p62/SQSTM1-dependent selective autophagy (25). Moreover, it has been demonstrated that constant p62 levels, due to autophagy defects, were enough to alter NF-κB regulation and gene expression, thereby stimulating tumor generation (26).…”