Abstract
The mosquito Aedes aegypti can spread the dengue, chikungunya and yellow fever viruses. Thus, the search for key molecules involved in the mosquito survival represents today a promising vector control strategy. High Mobility Group Box (HMGB) proteins are essential nuclear factors that maintain the high-order structure of chromatin, keeping eukaryotic cells viable. Outside the nucleus, secreted HMGB proteins could alert the innate immune system to foreign antigens and trigger the initiation of host defenses. In this work, we cloned and functionally characterized the HMGB1 protein from Aedes aegypti (AaHMGB1). The AaHMGB1 protein typically consists of two HMG-box DNA binding domains and an acidic C-terminus. Interestingly, AaHMGB1 contains a unique alanine/glutamine-rich (AQ-rich) C-terminal region that seems to be exclusive of dipteran HMGB proteins. AaHMGB1 is localized to the cell nucleus, mainly associated with heterochromatin. Circular dichroism analyses of AaHMGB1 or the C-terminal truncated proteins revealed α-helical structures. We showed that AaHMGB1 can effectively bind and change the topology of DNA, and that the AQ-rich and the C-terminal acidic regions can modulate its ability to promote DNA supercoiling, as well as its preference to bind supercoiled DNA. AaHMGB1 is phosphorylated by PKA and PKC, but not by CK2. Importantly, phosphorylation of AaHMGB1 by PKA or PKC completely abolishes its DNA bending activity. Thus, our study shows that a functional HMGB1 protein occurs in Aedes aegypt and we provide the first description of a HMGB1 protein containing an AQ-rich regulatory C-terminus.
Highlights
It is mandatory to eukaryotic cells to condense and organize their genomic DNA in a supramolecular nucleoprotein structure called chromatin, a conserved structural polymer of DNA and histones whose basic unit is the nucleosome [1]
Domain analysis showed that A. aegypti HMGB1 (AaHMGB1) contains the three part-domain organization typical of the High Mobility Group Box (HMGB) family, consisting of two HMG-box motifs, A and B, and a C-terminal acidic tail (Figure S1)
It is worth to mention that in spite of the AQ-rich domain be found only in dipterans, not all dipterans contain such a domain
Summary
It is mandatory to eukaryotic cells to condense and organize their genomic DNA in a supramolecular nucleoprotein structure called chromatin, a conserved structural polymer of DNA and histones whose basic unit is the nucleosome [1]. Dynamic changes in the local or global organization of chromatin are required to perform nuclear activities, including DNA replication, transcription and repair [2,3] Maintenance of such a dynamic structure in terms of proper nucleosome distribution and reorganization during nuclear activities is considered crucial to cell survival. HMGBs play biologically fundamental roles including DNA transcription, replication, repair and recombination [3,4,5]. These proteins act as DNA chaperones, which facilitate assembly of nucleoprotein higher-order chromatin structures by bending or looping DNA or by stabilizing underwound DNA [6]. Examples of transcription factors that interact with HMGB1 and enhance transcription are the steroid receptors [7,8], NF-kB/Rel [9], p53 [10], among others
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