Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy

Krisenko, Mariya O.; Higgins, Reneé; Ghosh, Soumitra; Zhou, Qing; Trybuła, J; Wang, Wen‐Horng; Geahlen, Robert L.

doi:10.1074/jbc.m115.642900

Cited by 44 publications

(42 citation statements)

References 57 publications

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“…A more recent study adds to the mechanism of SG clearance in human cells by describing a tyrosine kinase, SYK, which together with its binding partner GRB7 associates with SGs and promotes granulophagy. 127 SYK is not needed for SG formation, but is recruited to SGs upon its phosphorylation, in turn causing the phosphorylation of proteins at or near SGs and promoting their clearance via autophagy once the stress is relieved. This process was further shown to promote cellular survival.…”

Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

“…This process was further shown to promote cellular survival. 127 What clearly pans out from such studies is that eukaryotic cells are equipped with a robust means of SG clearance via autophagy, which must be kept finely tuned due to its physiological importance for cellular viability. 127,128 RNA as autophagic cargo-general considerations.…”

Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

“…127 What clearly pans out from such studies is that eukaryotic cells are equipped with a robust means of SG clearance via autophagy, which must be kept finely tuned due to its physiological importance for cellular viability. 127,128 RNA as autophagic cargo-general considerations. Interpreting the effects of autophagy-modulated changes on RNA, whether it be via ribophagy, granulophagy or other routes, is complicated by the fact that many types of cellular stress, including autophagy-inducing stress, can modulate translation and thereby also RNA metabolism through several mechanisms.…”

Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

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Emerging connections between RNA and autophagy

2016

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Macroautophagy/autophagy is a key catabolic process, essential for maintaining cellular homeostasis and survival through the removal and recycling of unwanted cellular material. Emerging evidence has revealed intricate connections between the RNA and autophagy research fields. While a majority of studies have focused on protein, lipid and carbohydrate catabolism via autophagy, accumulating data supports the view that several types of RNA and associated ribonucleoprotein complexes are specifically recruited to phagophores (precursors to autophagosomes) and subsequently degraded in the lysosome/vacuole. Moreover, recent studies have revealed a substantial number of novel autophagy regulators with RNA-related functions, indicating roles for RNA and associated proteins not only as cargo, but also as regulators of this process. In this review, we discuss widespread evidence of RNA catabolism via autophagy in yeast, plants and animals, reviewing the molecular mechanisms and biological importance in normal physiology, stress and disease. In addition, we explore emerging evidence of core autophagy regulation mediated by RNA-binding proteins and noncoding RNAs, and point to gaps in our current knowledge of the connection between RNA and autophagy. Finally, we discuss the pathological implications of RNA-protein aggregation, primarily in the context of neurodegenerative disease.

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Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

Section: Clearance Of Ribonucleoprotein Granules By Autophagymentioning

confidence: 99%

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Emerging connections between RNA and autophagy

2016

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“…This process would be similar to “granulophagy”, a selective autophagy process that the leads to the degradation of SG, PB, and other RNA granules (Buchan et al, 2013; Frankel et al, 2017). Granulophagy was first discovered in yeast, but also is widely observed in metazoan cells, and defects in this process has been linked to disease states such as Amyotrophic Lateral Sclerosis (Buchan et al, 2013; Krisenko et al, 2015; Monahan et al, 2016; Chitiprolu et al, 2018). While the autophagic degradation of RNA granules in plants is less well studied, granulophagy has been proposed as part of the plant host’s defense response during viral infection (Hafren et al, 2018), and in general has been postulated to be a component of plant RNA quality control (Yoon and Chung, 2019).…”

Section: Discussionmentioning

confidence: 99%

Regulator of Gene Silencing-Calmodulin associates with mRNA granules and the autophagy protein ATG8

Conner

Lokdarshi

Roberts

2019

Preprint

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“…We have recently demonstrated that induction of EMT by TGFb induces the formation of cytoplasmic RNA-processing complexes called P-bodies, and clearance of P-bodies through autophagy is required for reversal of EMT (15). On the basis of our previous identification of a role for SYK in promoting stress granule clearance through autophagy and our identification of multiple P-body proteins as SYK substrates, we next sought to assess a role for SYK in P-body formation and clearance (11,27). Expression of mCherry-labeled SYK results in a cellular diffuse localization (Fig.…”

Section: Syk Is Present In P-bodies and Facilitates Their Clearance Dmentioning

confidence: 99%

Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer

et al. 2019

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The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGFb to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFb-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells.

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Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy

Cited by 44 publications

References 57 publications

Emerging connections between RNA and autophagy

Emerging connections between RNA and autophagy

Regulator of Gene Silencing-Calmodulin associates with mRNA granules and the autophagy protein ATG8

Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer

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