The histone acetyl transferase LdHAT1 fromLeishmania donovaniis regulated by S-phase cell cycle kinase

Abstract

Histone acetyl transferases (HATs) are important histone modifiers that affect critical cellular processes like transcription, DNA replication and repairs through highly dynamic chromatin remodelling. Our earlier studies recognized LdHAT1 as a substrate of the S-phase cell cycle kinase LdCyc1-CRK3 from Leishmania donovani. Here, we confirm through site-directed mutagenesis that RXL-like cyclin-binding (Cy) motif dependent interaction of LdHAT1 with LdCyc1 is essential for its phosphorylation at a canonical Cdk target site by the kinase complex. LdHAT1 acetylates K10 residue of a peptide derived from L. donovani histone H4 N-terminal tail. Interestingly, phosphorylation of LdHAT1 by the S-phase kinase inhibits its H4K10 acetylation activity, implicating an important mechanism of periodic regulation of histone acetylation during cell cycle progression.

Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response

“…Modulation of H3 modification itself may be transcriptionally regulated, as suggested by previous transcriptomics analyses that revealed changes in HDAC expression in L. am-infected BMDMs (Calegari-Silva et al, 2018;Osorio y Forté a et al, 2009). Likewise, the release of parasite histones (Silverman et al, 2010) may alter host H3 modification through competition with host HMEs, and host histones may be directly modified by parasite HMEs, such as SIRTUIN 2 (Ronin et al, 2018;Tavares et al, 2010;Yahiaoui et al, 1996) or various histone acetyltransferases (Chandra et al, 2017;Kumar et al, 2012;Kumar and Saha, 2015;Maity and Saha, 2012). Future studies investigating macrophage-Leishmania interactions at the systems level combining transcriptomic, epigenetic, and metabolomic analyses will shed new light on the mechanisms underlying host cell chromatin remodeling, with the potential to uncover new candidates for host-directed, anti-leishmanial therapy.…”

Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives

“…12 Furthermore, parasitic lysine acetyl transferase has been validated as a therapeutic target for kinetoplastids. 13,14 As part of a new program toward the development of trypanocidal and antileishmanial agents and taking into consideration the similarities regarding the polyamine dependence of both cancer cells and kinetoplastids, we became interested in testing our polyaminated compounds against these parasites. Among our series of polyamines, the most potent antitrypanosomal agents was the polyamine derivative 1 where the coenzyme A was partially truncated (Fig.…”

Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery

“…donovani histone H4. Both HAT1 and HAT2 have been found to acetylate H4K10, , while H4K4 is an acetylation site of HAT2 and HAT3. , Additionally, H4K14 was identified as a major acetylation site and H4K2 as a potential minor acetylation site of HAT4 . Peptides from histone H4 were therefore investigated alongside those from histone H2B in the search for BDF5 binding sequences.…”