Giant Cellular Vacuoles Induced by Rare Earth Oxide Nanoparticles are Abnormally Enlarged Endo/Lysosomes and Promote mTOR-Dependent TFEB Nucleus Translocation.
Many nanomaterials are reported to disrupt lysosomal function and homeostasis, but how cells sense and then respond to nanomaterial-elicited lysosome stress is poorly understood. Nucleus translocation of transcription factor EB (TFEB) plays critical roles in lysosome biogenesis following lysosome stress induced by starvation. The authors previously reported massive cellular vacuolization, along with autophagy induction, in cells treated with rare earth oxide (REO) nanoparticles. Here, the authors identify these giant cellular vacuoles as abnormally enlarged and alkalinized endo/lysosomes whose formation is dependent on macropinocytosis. This vacuolization causes deactivation of mammalian target of rapamycin (mTOR), a TFEB-interacting kinase that resides on the lysosome membrane. Subsequently, TFEB is dephosphorylated at serine 142 and translocated into cell nucleus. This nucleus translocation of TFEB is observed only in vacuolated cells and it is critical for maintaining lysosome homeostasis after REO nanoparticle treatment, as knock-down of TFEB gene significantly compromises lysosome function and enhances cell death in nanoparticle-treated cells. Our results reveal that cellular vacuolization, which is commonly observed in cells treated with REOs and other nanomaterials, represents a condition of profound lysosome stress, and cells sense and respond to this stress by facilitating mTOR-dependent TFEB nucleus translocation in an effort to restore lysosome homeostasis.
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Jun
J
Lin
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Shan-Shan
SS
Shi
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Ji-Qian
JQ
Zhang
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Yun-Jiao
YJ
Zhang
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, P. R. China.
Li
L
Zhang
Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui, 230031, P. R. China.
Yun
Y
Liu
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Pei-Pei
PP
Jin
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Peng-Fei
PF
Wei
Core Facility Center of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China. rhsh@ustc.edu.cn.
Rong-Hua
RH
Shi
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China. zhouweid@ustc.edu.cn.|School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui, 230009, P. R. China. zhouweid@ustc.edu.cn.
Wei
W
Zhou
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China. lpwen@ustc.edu.cn.
Long-Ping
LP
Wen
D000468:Alkalies / Q000737:chemistry; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008674:Metals, Rare Earth / Q000737:chemistry*; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D010873:Pinocytosis; D021381:Protein Transport; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism*
D000468:Alkalies; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008674:Metals, Rare Earth; D010087:Oxides; C064972:TFEB protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
lysosome biogenesis; mTORC1; macropinocytosis; rare earth oxide nanoparticles; transcription factor EB (TFEB); yttrium oxide