MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF‐β–activated kinase 1‐dependent activation of the transcription factor EB

Abstract

Lysosome has a crucial role in clearance of endocytosed pathogens from the cell. Small molecules that can boost lysosome function and bactericidal ability to cope with subsequent infection are urgently needed. Here, we report that MPB, a novel berberine derivative, induced lysosome-based degradation and clearance of methicillin-resistant Staphylococcus aureus and enteroinvasive Escherichia coli in macrophages. MPB caused nuclear translocation of transcription factor EB (TFEB), which boosted expression of lysosome genes. TFEB silencing repressed the MPB-mediated enhancements in degradation and bacterial eradication. MPB switched on TFEB nuclear translocation by coupling 2 parallel signaling pathways. MPB-triggered JNK activation led to 14-3-3δ being released from TFEB, which, in turn, caused TFEB nuclear translocation. In addition, MPB induced AMPK activation and subsequent inhibition of mechanistic target of rapamycin activity, which also contributed to TFEB nuclear translocation. Importantly, genetical or pharmaceutical inhibition of TGF-β-activated kinase 1 (TAK1) reduced MPB action remarkably. MPB acted through TAK1 at lysine 158 to activate JNK and AMPK and, thus, induced TFEB-dependent bactericidal activity in macrophages. Therefore, our study reveals a novel mechanism by which MPB controls JNK and AMPK phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158-dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection.-Liu, X., Zhang, N., Liu, Y., Liu, L., Zeng, Q., Yin, M., Wang, Y., Song, D., Deng, H. MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-β-activated kinase 1-dependent activating the transcription factor EB.

The Interplay of Host Lysosomes and Intracellular Pathogens

“…Further, genetic or chemical modulation of the host lysosomes correspondingly affected the intracellular survival of Salmonella suggesting that the intracellular growth of Salmonella is affected by the lysosomes (McGourty et al, 2012). Several other studies have also reported that the chemical or genetic enrichment of lysosomes enhances bactericidal properties and bacterial clearance of other pathogens such as Burkholderia cenocepacia, methicillin-resistant Staphylococcus aureus and enteroinvasive Escherichia coli (Sogi et al, 2017;Vural et al, 2018;Liu et al, 2019). These studies show an emerging consensus with these limited examples of the global content of lysosomes in cells having a growth inhibitory effect on intracellular pathogens.…”

The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

“…TFEB is involved in host response by regulating both innate and adaptive immunity ( Brady et al, 2018b ; Irazoqui, 2020 ). It has been documented that TFEB participates in the process of macrophage activation by following mechanisms ( Fang L. et al, 2017 ), including promoting bactericidal function ( Gray et al, 2016 ; Liu X. et al, 2019 ) and facilitating the production of various proinflammatory mediators ( Visvikis et al, 2014 ; Pastore et al, 2016 ; Figure 2Ca ). TFEB is demonstrated to play a role in innate immune response by modulating xenophagy, a form of selective autophagy targeting invaded microorganisms ( Wang and Li, 2020 ).…”

Boosting the autophagy‐lysosomal pathway by phytochemicals: A potential therapeutic strategy against Alzheimer's disease

“…The referred study revealed a novel mechanism by which MPB controls jun N-terminal kinase (JNK) and AMP-activated protein kinase (AMPK) phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158-dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection. 118 In the last few years, there has been extensive progress on understanding autophagy regulators from natural products, which provide new insights into the development of treatment strategies for AD by targeting autophagy in animal models. In the present review, we provide an overview of current research assessing the role of autophagy in AD, including the regulation mechanisms of ALP and the therapeutic potential of herbal medicine in AD by targeting autophagy.…”

“…Recently, researchers have shown thatMPB, a novel berberine derivative, induced lysosome‐based degradation and clearance of methicillin‐resistant Staphylococcus aureus and Escherichia coli in macrophages. The referred study revealed a novel mechanism by which MPB controls jun N‐terminal kinase (JNK) and AMP‐activated protein kinase (AMPK) phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158‐dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection 118 . In the last few years, there has been extensive progress on understanding autophagy regulators from natural products, which provide new insights into the development of treatment strategies for AD by targeting autophagy in animal models.…”