Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

Abstract

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.

Identification of Potential miRNA–mRNA Regulatory Network Associated with Pig Growth Performance in the Pituitaries of Bama Minipigs and Landrace Pigs

“…In miR-4334-5p- STAT3/PIK3R1/RPS6KA3/CAB39L : STAT3 is a key signaling protein that triggers a variety of biological outcomes including cell growth, differentiation, and survival [ 41 ]; PIK3R1 mediated the PI3K/AKT/mTOR signaling pathway to promote cell proliferation and inhibit apoptosis [ 42 ]; and RPS6KA3 mediated cell proliferation, survival, and differentiation by regulating the mTOR signaling and inhibiting the pro-apoptotic functions of BCL2-associated agonist of cell death ( BAD ) and death-associated protein kinase 1 ( DAPK1 ) [ 43 ]. miR-4334 has been confirmed to target Toll-like receptor 4 ( TLR4 ), and the knockdown of TLR4 inhibited the angiotensin II-induced proliferation of vascular smooth muscle cells [ 44 , 45 ].…”

Epigenetics in Tuberculosis: Immunomodulation of Host Immune Response

“…These modifications carried out by isoniazid can lead to malignancies. Thus, through more epigenetic studies, many more mechanisms of such iatrogenic reactions to anti-TB drugs can be explained [ 135 ]. The Mtb pathogen also utilizes various epigenetic processes to proliferate in host, which can be targeted effectively as a therapeutic option.…”

Chemical Biology Tools for Protein Lysine Acylation

“…Further pull-down experiments with cell lysates allowed the successful identification of 475 and 472 putative substrates of p300 and GCN5, respectively. Among them, two novel substrates of GCN5, Kcr p300 [28] CBP, PCAF hMOF [29] WB; IP/WB Sirt1 [44] Sirt1-3 [46] HDAC1 & 3 [29] HDAC1-3 & 8 [44] IF/WB AfBP IP/WB IF/WB AF9 [89] YEATS2 [91] MOZ/DPF2 [92] Taf14 [90] ITC/Microarray/X-ray/IP X-ray/NMR/Pull-Down Ksucc GCN5 [30] p300 [34] IP-MS WB Sirt5 [20] Sirt7 [21] LC-MS/MS/X-ray IP/LC-MS/MS GAS41 [93] Pull-Down/X-ray Kmal NA NR Sirt5 [20] LC-MS/MS/X-ray NA NR Kglu GCN5 [35] IP/WB Sirt5 [47] Sirt7 [35] FL probe/LC-MS/WB MCR/WB/LC-MS/MS NA NR Khib p300 [31] Tip60 [32] WB/IF WB/MS HDAC2 [32] HDAC3 [32] WB/MS NA NR Kbhb p300 [33] WB HDAC1 & 2 [33] Sirt3 [53] WB/LC X-ray/WB NA NR Klip LIPT1-2 [22][23] WB Sirt4 [8] Sirt2 [48] IP/LC-MS/MS AfBP NA NR Kmyr NMT1-2 [24] LC-MS/X-ray /MCR HDAC8 [50] , Sirt2 [25] Sirt6 [26] , Sirt7 [52] MCR NA NR Kbz NA NR Sirt2 [4] LC-MS/WB DPF, YEATS [27] ITC/Microarray/X-ray/IF Kla p300 [2] LC-MS/WB HDAC1 & 3 [126] FL Probe/WB NA NR Kinic CBP, p300 [5] WB HDAC3 [5] IF namely the structural...…”

“…Recently, new types of lysine acylation, including crotonylation (Kcr), malonylation (Kmal), succinylation (Ksucc), 2-hydroxyisobutyrylation (Khib), benzoylation (Kbz), lactylation (Kla) and isonicotinylation (Kinic), have been identified with the advancement in mass spectrometry, and exhibit intriguing biological functions in metabolism and epigenetics (Figure 1A). [1][2][3][4][5] Lysine PTMs are associated with gene transcription, DNA repair, signal transduction, protein stability and functions, and metabolism. [6] Molecular mechanisms of dynamic dysregulation of lysine PTMs are known to be closely associated with many human diseases, most notably cancer.…”