Inhibition of the ULK1 protein complex suppresses Staphylococcus-induced autophagy and cell death

Radhi, Ohood Aqeed; Davidson, Scott; Scott, Fiona L.; Zeng, Renpan; Jones, D. Heulyn; Tomkinson, Nicholas C. O.; Yu, Jun; Chan, Edmond Y W

doi:10.1074/jbc.ra119.008923

Cited by 9 publications

(8 citation statements)

References 77 publications

(120 reference statements)

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“…ULK1 and EGFR levels in patients with normoalbuminuria are significantly higher than in microalbuminuria and macroalbuminuria [113]. ULK1 plays an important role in protecting hosts from infection by pathogens; inhibition of ULK1 expression prevents the death of host cells infected by Staphylococcus aureus [114].…”

Section: The Noncanonical Role Of Ulk1mentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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Section: The Noncanonical Role Of Ulk1mentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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“…Lipidated autophagy-related protein (LC3B-II) conjugates are greatly enriched in epithelial cells infected with Staphylococcus. Inhibition of the autophagy-activating kinase 1 (ULK1) suppresses Staphylococcus-induced autophagy and Staphylococcus intracellular replication (112). S. aureus also is also able to escape from LC3B labeled autophagosomes, in part by impeding the maturation of autophagosomes.…”

Section: Staphylococcus Aureusmentioning

confidence: 99%

Competitive Cell Death Interactions in Pulmonary Infection: Host Modulation Versus Pathogen Manipulation

2020

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In the context of pulmonary infection, both hosts and pathogens have evolved a multitude of mechanisms to regulate the process of host cell death. The host aims to rapidly induce an inflammatory response at the site of infection, promote pathogen clearance, quickly resolve inflammation, and return to tissue homeostasis. The appropriate modulation of cell death in respiratory epithelial cells and pulmonary immune cells is central in the execution of all these processes. Cell death can be either inflammatory or anti-inflammatory depending on regulated cell death (RCD) modality triggered and the infection context. In addition, diverse bacterial pathogens have evolved many means to manipulate host cell death to increase bacterial survival and spread. The multitude of ways that hosts and bacteria engage in a molecular tug of war to modulate cell death dynamics during infection emphasizes its relevance in host responses and pathogen virulence at the host pathogen interface. This narrative review outlines several current lines of research characterizing bacterial pathogen manipulation of host cell death pathways in the lung. We postulate that understanding these interactions and the dynamics of intracellular and extracellular bacteria RCD manipulation, may lead to novel therapeutic approaches for the treatment of intractable respiratory infections.

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“…However, these pathogens as well as many other pathogens such as Escherichia coli have been reported to manipulate or subvert the autophagic pathway for survival (57)(58)(59)(60)(61). Moreover, many studies have described divergent mechanisms for S. aureus intracellular survival and replication using the autophagic pathway in both nonprofessional and professional phagocytes, with several autophagy inhibitors such as VPS34-IN1 and 3-methyladenine shown to reduce intracellular survival of S. aureus across a range of cell types (10,21,62,63). In a study by Schnaith et al, S. aureus survived and replicated in autophagosomes within HeLa cells (33).…”

Section: Autophagy Is a Key Mechanism For The Intracellular Survival Of S Aureusmentioning

confidence: 99%

“…Intracellular survival was followed by eventual escape into the cytoplasm coupled with caspase-independent, ATG5-dependent host cell death with high levels of vacuolization, indicative of autophagic cell death. Recently, the induction of autophagy in HeLa cells by S. aureus was compared to Salmonella infection, which is known to evade the autophagy pathway to facilitate intracellular survival ( 62 , 64 ). While both bacteria showed an ability to survive intracellularly, S. aureus escaped from lysosomal compartments with less lysosomal membrane damage compared to Salmonella , suggesting that S. aureus may actively and specifically subvert the xenophagy defence pathway.…”

Section: Autophagy Is a Key Mechanism For The Intracellular Survival Of S Aureusmentioning

confidence: 99%

Making the Most of the Host; Targeting the Autophagy Pathway Facilitates Staphylococcus aureus Intracellular Survival in Neutrophils

2021

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The success of Staphylococcus aureus as a human commensal and an opportunistic pathogen relies on its ability to adapt to several niches within the host. The innate immune response plays a key role in protecting the host against S. aureus infection; however, S. aureus adeptness at evading the innate immune system is indisputably evident. The “Trojan horse” theory has been postulated to describe a mechanism by which S. aureus takes advantage of phagocytes as a survival niche within the host to facilitate dissemination of S. aureus to secondary sites during systemic infection. Several studies have determined that S. aureus can parasitize both professional and non-professional phagocytes by manipulating the host autophagy pathway in order to create an intracellular survival niche. Neutrophils represent a critical cell type in S. aureus infection as demonstrated by the increased risk of infection among patients with congenital neutrophil disorders. However, S. aureus has been repeatedly shown to survive intracellularly within neutrophils with evidence now supporting a pathogenic role of host autophagy. By manipulating this pathway, S. aureus can also alter the apoptotic fate of the neutrophil and potentially skew other important signalling pathways for its own gain. Understanding these critical host-pathogen interactions could lead to the development of new host directed therapeutics for the treatment of S. aureus infection by removing its intracellular niche and restoring host bactericidal functions. This review discusses the current findings surrounding intracellular survival of S. aureus within neutrophils, the pathogenic role autophagy plays in this process and considers the therapeutic potential for targeting this immune evasion mechanism.

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Inhibition of the ULK1 protein complex suppresses Staphylococcus-induced autophagy and cell death

Cited by 9 publications

References 77 publications

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Competitive Cell Death Interactions in Pulmonary Infection: Host Modulation Versus Pathogen Manipulation

Making the Most of the Host; Targeting the Autophagy Pathway Facilitates Staphylococcus aureus Intracellular Survival in Neutrophils

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