Biology subjects

Kang, B. G.

Publications and source records attributed to Kang, B. G..

3 recordsLinked to original sources

bioRxiv2023

Histone H1.2 Dependent Translocation of Poly (ADP-ribose) Initiates Parthanatos

Toxic cellular insults activate the nuclear protein poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) to initiate parthanatos, a regulated cell death program. PAR acts as a death signal by translocating from the nucleus to the cytosol, where it activates the next steps in the parthanatic cell death cascade. How PAR translocates from the nucleus to the cytosol is not known. Here we show that PARylation and PAR binding to histone H1.2 enables it to act as a carrier, transporting PAR out of the nucleus to the cytosol. Knocking down the expression of histone H1.2 via CRISPR/Cas9 and knockout of histone H1.2 reduces the translocation of PAR to the cytosol after treatment of human cortical neurons with N-methyl-D-aspartate (NMDA) or following oxygen-glucose deprivation (OGD). The PAR-dependent E3 ubiquitin ligase, Iduna (RNF146) ubiquitinates PARylated H1.2. Overexpression of Iduna reduces the expression levels of cytosolic histone H1.2, preventing the translocation of PAR following NMDA or OGD exposure, similar to inhibition of PAR formation by the PARP inhibitor, DPQ. Whereas, the catalytically null variant Iduna C60A, or the PAR binding mutant Iduna Y156A and R157A (YRAA) was ineffective in ubiquitinating histone H1.2 and preventing the reduction in cytosolic histone H1.2 levels and PAR translocation from the nucleus to the cytosol. Histone H1.2 heterozygote and homozygote knockout mice exhibited reduced infarct volume 24 hrs post middle cerebral artery occlusion (MCAO) and showed better recovery in motor deficits than wildtype littermates at day 3 and/or day 7 post MCAO. Collectively, these findings reveal histone H1.2 as the key carrier of PAR out of the nucleus to the cytosol where it participates in the next step of the parthanatic cell death cascade.

cell biology↗

bioRxiv2022

Proteome-wide microarray-based screening of PAR-binding proteins

Poly(ADP-ribose) (PAR) plays a crucial role in intracellular signaling and scaffolding through covalent modification or non-covalent binding to target proteins. The non- covalent binding PARylome has not been extensively characterized. Here we performed a PAR-binding screen using a human protein microarray that covers most of the human proteome to characterize the non-covalent binding PARylome. A total of 356 PAR- binding proteins were identified. The PAR-binding PARylome suggests that PAR- binding regulates a variety of biological processes beyond well-characterized DNA damage signaling and DNA repair. Proteins that may be reprogrammed by PAR-binding include signaling molecules, transcription factors, nucleic acid binding proteins, calcium binding proteins, ligases, oxidoreductases, enzymes, transferases, hydrolases, and receptors. The global database of PAR-binding proteins that we established will be a valuable tool for further in-depth analysis of the role of PARylation in a wide range of biological contexts.

biochemistry↗

bioRxiv2021

Host regulator PARP1 contributes to sex differences and immune responses in a mouse model of tuberculosis

Tuberculosis (TB) is a devastating infectious disease responsible for nearly 2 million deaths annually that has a poorly understood male bias. Elucidating the basis of this male bias may enable precision medicine interventions for TB treatment and prevention. Here, we identify the master regulator Poly(ADP-ribose) Polymerase 1 (PARP1) as a driver of TB sex differences. We found that infection with M. tuberculosis (M. tb) triggers robust PARP activation in mouse lungs, suggesting that PARP1 activation is a fundamental host response to TB. Remarkably, PARP1 deletion abolished known sex differences in TB cytokine responses and blunted the early induction of TNF, IL-1{beta}, IFN{gamma}, MCP-1, and IL-6, particularly in male mice. In contrast, PARP1 was required for IL-10 induction in male or female mice. PARP1 deletion was protective against TB in female mice, resulting in significantly prolonged survival and reduced bacterial burden, but impaired TB containment in male mice. Our findings indicate that PARP1 contributes to TB sex differences via sexually divergent immune regulation and uniquely enhances early proinflammatory responses in males that prove beneficial for TB containment.

immunology↗