Hip1 Modulates Macrophage Responses through Proteolysis of GroEL2

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Mycobacterium tuberculosis (Mtb) faces adverse conditions within host cells and has evolved many mechanisms to adapt quickly to the hostile immune environment. We have previously shown that an Mtb factor, Hip1, is important for Mtb virulence and for modulating host immunity. While Hip1 was predicted to be a protease, its enzymatic activity and molecular mechanism of function remained unclear. We have now characterized the biochemistry of Hip1 and conclusively show that Hip1 is a serine protease that can process peptide substrates. Further, we have identified a physiological target for Hip1 activity in Mtb, the Mtb chaperone-like protein GroEL2. Interestingly, cleavage of GroEL2 by Hip1 converted GroEL2 from a multimeric cell wall-associated protein to a monomeric form that is secreted extracellularly. Importantly, we show that cleavage of GroEL2 by Hip1 is biologically relevant and promotes dampening of macrophage responses during Mtb infection. Thus, our studies have uncovered a fine-tuned strategy of immune modulation at the protein level that involves regulating Hip1-GroEL2 interactions and provide key molecular insights for targeting Hip1 protease activity for inhibition.

Vyšlo v časopise: Hip1 Modulates Macrophage Responses through Proteolysis of GroEL2. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004132
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004132

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