Compartmentalized, Functional Role Of Angiogenin During Rickettsioses: Evidence Of Possible Mediation By Host TRNA-derived Small Noncoding RNAs | 16402
Journal of Clinical & Experimental Pathology
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Microvascular endothelial barrier dysfunction is the central enigma in rickettsioses. Angiogenin (ANG) is one of the
earliest identified angiogenic factors, of which some are relevant to the phosphorylation of VE-cadherins that serve as
endothelial adherens proteins. Besides its nuclear role, ANG is thought to play a cytoplasmic role, owing to its RNase activity
that cleaves tRNA to produce small RNAs. Recently, such tRNA-derived RNA fragments (tRFs) have been shown to be induced
under stress conditions. All these observations raise an intriguing hypothesis about a novel cytoplasmic role of ANG, which is
induced upon infection with
and generates tRFs that may play roles in rickettsioses.
C3H/HeN mice were infected intravenously with a sublethal dose of
IFstudies of R. and ANG.HUVEC cells
were infected with
before incubation with 1μg/ml ANG. HUVEC samples were subjected to IF, exogenous ANG
translocation, endothelial permeability, and immunoprecipitation phosphorylation assays. To identify small non-coding
RNAs (sncRNAs) upon rickettsial infection, RNAs from pulverized mouse lung tissues and HUVECs were subjected to library
preparation and deep sequencing analysis using an Illumina 2000 instrument. Identified sncRNAs were confirmed by Northern
hybridization, and their target mRNAs were predicted
using BLAST and RNAhybrid programs.
We have demonstrated endothelial up-regulation of ANG, co-localized with rickettsial infection
. We also have provided
direct evidence that rickettsial infection sensitizes HUVECs to the translocation of exogenous ANG in a compartmentalized
pattern at different times post-infection. Typically, exogenous ANG translocates into the nucleus at 24 hrs and to the cytoplasm
at 72 hrs post-infection. The ANG cytoplasmic translocation enhances phosphorylation and destabilization of VE-cadherin
and attenuates endothelial barrier function. Of note, deep sequencing analysis detected tRFs, mostly derived from the 5?-halves
of host tRNAs, that are induced by ANG. Northern hybridization validates the two most abundantly cloned tRFs derived from
tRNA-ValGTG and tRNA-GlyGCC, in both mouse tissues and human cells. Bioinformatics analysis predicted that these tRFs
may interact with transcripts associated with the endothelial barrier, the host cell inflammatory response, and autophagy.
Our data provide new insight into the role of compartmentalized ANG during SFG rickettsioses, and highlight its possible
mediation through tRFs.
Bin Gong has completed his MD and Ph.D. at the age of 29 years from the Second Military Medical College in Shanghai, China and Postdoctoral studies at the
University of Texas Medical Branch at Galveston. He is an Assistant Professor in the Department of Pathology and the Director of Experimental Pathology and
sncRNA omicscore at the Galveston National Laboratory at the UTMB. He has published more than 25 papers and has been serving as an editorial board member
of reputed journals.
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