# The gram-positive HtrA, the protease that is also a chaperone

## TL;DR

This paper reviews the role of HtrA in gram-positive bacteria, highlighting its dual function as a chaperone and protease and its potential as a target for new antibiotics.

## Contribution

The paper identifies current knowledge gaps in HtrA regulation and function in gram-positive bacteria and emphasizes the need for further research.

## Key findings

- HtrA in gram-positive bacteria is involved in envelope integrity, stress resistance, and virulence.
- HtrA's role in competence, biofilm dynamics, and host protein degradation is well-documented.
- Structural and regulatory information gaps hinder the development of HtrA-targeted antibiotics.

## Abstract

High-temperature requirement A (HtrA) aids in protein homeostasis by playing a key dual role as a chaperone and protease. HtrA ensures protein folding quality control during secretion and protects cells against protein aggregation by degrading misfolded proteins. HtrA proteins are typically composed of a protease domain and at least one PDZ domain, proposed to help regulate their activity and interactions with substrates. In gram-positive bacteria, HtrA contributes to critical cellular functions and has been linked to processes such as maintaining envelope integrity, stress resistance, and virulence. In addition, HtrA has been shown to contribute to the modulation of competence and biofilm dynamics as well as the degradation of host proteins in infection models. In some gram-positive bacteria, HtrA expression is regulated by two-component systems, but many HtrA upstream signals and downstream targets remain unclear. As antibiotic resistance continues to rise, HtrA is gaining attention as a promising target of inhibition for new antibacterial strategies. However, a lack of structural information, unclear regulatory mechanisms, and unknown substrates make designing effective HtrA inhibitors challenging. This review highlights these knowledge gaps and aims to spark more focused research on HtrA in gram-positive species.