An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis
An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis
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DOI：
10.1073/pnas.1423319112
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发表时间：
2015-04-07
影响因子：
11.1
通讯作者：
Darwin, K. Heran
中科院分区：
文献类型：
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作者：
Jastrab, Jordan B.;Wang, Tong;Darwin, K. Heran
结核分枝杆菌编码一种与真核蛋白酶体高度相似的蛋白酶体，并且是引起动物致命感染所必需的。唯一已知的靶蛋白降解细菌中的蛋白酶体的途径是pupylation，这是功能上类似于真核泛素化。然而，有证据表明，M。结核蛋白酶体也有助于不依赖于蛹化的途径。为了鉴定新的蛋白酶体辅助因子，我们分离了与M.发现了一个以前没有特征的蛋白质Rv 3780，它形成环并覆盖M。结核蛋白酶体核心颗粒。Rv 3780以腺苷三磷酸（ATP）非依赖性方式增强蛋白酶体对肽和蛋白质的降解。我们确定了假定的Rv 3780依赖性蛋白酶体底物，并发现Rv 3780促进了热休克蛋白阻遏物HspR的稳健降解。重要的是，M。结核Rv 3780突变体具有一般的生长缺陷，对热应激敏感，并且在小鼠中生长减弱。总的来说，这些数据表明，ATP-非依赖性蛋白酶体激活剂并不局限于真核生物，可以有助于世界上最具破坏性的病原体之一的毒力。
Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world's most devastating pathogens.