Oligomers of human histone chaperone NPM1 alter p300/KAT3B folding to induce autoacetylation

Publication date: August 2018
Source:Biochimica et Biophysica Acta (BBA) – General Subjects, Volume 1862, Issue 8
Author(s): Stephanie Kaypee, Smitha Asoka Sahadevan, Deepthi Sudarshan, Sarmistha Halder Sinha, Shilpa Patil, Parijat Senapati, Gopinath S. Kodaganur, Azeem Mohiyuddin, Dipak Dasgupta, Tapas K. Kundu
Backgroundp300 (KAT3B) lysine acetyltransferase activity is modulated under different physiological and pathological contexts through the induction of trans-autoacetylation. This phenomenon is mediated by several factors, mechanisms of which are not fully understood.MethodsThrough acetyltransferase assays using full-length, baculovirus-expressed KATs, the specificity of NPM1-mediated enhancement of p300 autoacetylation was tested. Chaperone assays and tryptophan fluorescence studies were performed to evaluate the NPM1-induced protein folding. The NPM1 oligomer-defective mutant characterization was done by glutaraldehyde-crosslinking. The small-molecule inhibitor of NPM1 oligomerization was used to confirm the absolute requirement of multimeric NPM1 in vivo. Immunohistochemistry analysis of oral cancer patient samples was done to uncover the pathophysiological significance of NPM1-induced p300 autoacetylation.ResultsWe find that the histone chaperone NPM1 is a specific inducer of p300 autoacetylation. Distinct from its histone chaperone activity, NPM1 is a molecular chaperone of p300. The biophysical experiments suggest that there is a reversible binding between NPM1 and p300 which can modulate p300 acetyltransferase activity. Disruption of NPM1 oligomerization suggests that oligomeric NPM1 is essential for the induction of p300 autoacetylation. Significantly, we observe a concomitant hyper-autoacetylation of p300 with overexpression of NPM1 in oral cancer samples.ConclusionNPM1 can specifically modulate p300 acetyltransferase activity through the enhancement of autoacetylation. The molecular chaperone activity and oligomerization of NPM1 play a pivotal role in this phenomenon.General significanceNPM1 is overexpressed in several solid cancers, the significance of which is unknown. Induction of p300 autoacetylation could be the cause of NPM1-mediated tumorigenicity.