HnRNPK and lysine specific histone demethylase-1 regulates IP-10 mRNA stability in monocytes

Kartiga Natarajan; Arun Sundaramoorthy; Narkunaraja Shanmugam

doi:10.1016/j.ejphar.2021.174683

HnRNPK and lysine specific histone demethylase-1 regulates IP-10 mRNA stability in monocytes

Eur J Pharmacol. 2022 Apr 5:920:174683. doi: 10.1016/j.ejphar.2021.174683. Epub 2021 Dec 13.

Authors

Kartiga Natarajan¹, Arun Sundaramoorthy², Narkunaraja Shanmugam³

Affiliations

¹ Diabetes and Cardiovascular Research Laboratory, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620 024, Tamilnadu, India.
² Diabetes and Cardiovascular Research Laboratory, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620 024, Tamilnadu, India. Electronic address: asmarun@bdu.ac.in.
³ Diabetes and Cardiovascular Research Laboratory, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620 024, Tamilnadu, India. Electronic address: nshanmugam@bdu.ac.in.

PMID: 34914972
DOI: 10.1016/j.ejphar.2021.174683

Abstract

Altered mRNA metabolism is a feature of many inflammatory diseases. Post transcriptional regulation of interferon-γ-inducible protein (IP)-10 has been uncharacterized in diabetes conditions. RNA-affinity capture method and RNA immuno-precipitation revealed S100b treatment increased the binding of heterogeneous nuclear ribonucleoprotein (hnRNP)K to the IP-10 3'UTR and increased IP-10 mRNA accumulation. Luciferase activity assay using reporter plasmids showed involvement of IP-10 3'UTR. Knocking down of hnRNPK destabilized S100b induced IP-10 mRNA accumulation. S100b promoted the translocation of hnRNPK from nucleus to the cytoplasm and this was confirmed by phosphomimetic S284/353D mutant and non-phosphatable S284/353A hnRNPK mutant. S100b treatment demethylates hnRNPK at Lys219 by Lysine Specific Demethylase (LSD)-1. HnRNPK^K219I, a demethylation defective mutant increased IP-10 mRNA stability. Apparently, triple mutant hnRNPK^{K219I/S284D/353D} promoted IP-10 mRNA stability. Interestingly, knocking down LSD-1 abolished S100b induced IP-10 mRNA accumulation. These observations show for the first time that IP-10 mRNA stability is dynamically regulated by Lysine demethylation of hnRNPK by LSD-1. These results indicate that hnRNPK plays an important role in IP-10 mRNA stability induced by S100b which could exacerbate monocyte activation, relevant to the pathogenesis of diabetic complications like atherosclerosis.

Keywords: IP-10; LSD-1; Non-histone demethylation; RAGE; hnRNPK; mRNA stability.

MeSH terms

Chemokine CXCL10* / genetics
Heterogeneous-Nuclear Ribonucleoprotein K* / metabolism
Histone Demethylases* / metabolism
Humans
Monocytes* / metabolism
RNA Stability*
RNA, Messenger* / chemistry

Substances

CXCL10 protein, human
Chemokine CXCL10
Heterogeneous-Nuclear Ribonucleoprotein K
RNA, Messenger
HNRNPK protein, human
Histone Demethylases
KDM1A protein, human