Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-11-13

AUTHORS

Xiufang Xiong, Xia Liu, Haomin Li, Hengqian He, Yi Sun, Yongchao Zhao

ABSTRACT

RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis. More... »

PAGES

1131

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41419-018-1168-7

DOI

http://dx.doi.org/10.1038/s41419-018-1168-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1109815836

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30425236


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42 schema:description RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
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49 DEPTOR
50 DEPTOR accumulation
51 DEPTOR degradation
52 DNA damage response
53 MB231
54 MEFs
55 Mechanistically
56 RPS27L
57 SK-BR3 cells
58 Skp1-Cullin
59 accumulation
60 activity
61 adjacent normal tissues
62 apoptosis
63 autophagy
64 autophagy induction
65 autophagy inhibitor
66 autophagy regulators
67 axis
68 bafilomycin A1
69 breast cancer
70 breast tumorigenesis
71 cancer
72 causal role
73 cells
74 cellular survival mechanism
75 chloroquine
76 damage response
77 degradation
78 deletion
79 disruption
80 genome instability
81 human breast cancer
82 inactivation
83 induction
84 inhibitors
85 instability
86 levels
87 ligase
88 loss
89 lymphomagenesis
90 mTORC1
91 mTORC1 axis
92 mechanism
93 mice
94 mutant p53
95 negative autophagy regulator
96 normal tissues
97 p53
98 p53 regulators
99 p53 targets
100 protein
101 radiation
102 receptors
103 reduction
104 regulator
105 response
106 ribosomal proteins
107 role
108 study
109 substrate receptor
110 survival mechanism
111 target
112 tissue
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114 ubiquitin ligase
115 β-TrCP
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