# HSP70 is a chaperone for IL-33 activity in chronic airway disease

## TL;DR

This study shows how HSP70 helps release and stabilize IL-33, a key inflammation driver in COPD and asthma, suggesting new therapeutic targets.

## Contribution

The study identifies HSP70 as a chaperone for unconventional secretion and stabilization of IL-33Δ34 in chronic airway diseases.

## Key findings

- IL-33Δ34 interacts with HSP70 and is secreted via phosphatidylserine and CUPS.
- Extracellular HSP70 stabilizes IL-33Δ34, enhancing its receptor binding and activity.
- Proteostasis network components like HSP70, HSP90, and CCT are dysregulated in COPD and asthma.

## Abstract

IL-33 is a key driver of type 2 inflammation and implicated in pathology of chronic obstructive pulmonary disease (COPD) and asthma. However, the mechanism for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. We previously reported an airway disease–associated isoform IL-33Δ34 that escapes nuclear sequestration and is tonically secreted from epithelial cells. Here, we describe how this IL-33Δ34 isoform interacts with HSP70 within cells and is targeted to secretory organelles through coordinated binding to phosphatidylserine (PS) and delivered to compartments for unconventional protein secretion (CUPS). Once secreted, extracellular HSP70 (eHSP70) in complex with IL-33Δ34 stabilizes the cytokine by inhibiting oxidation and degradation, which results in enhanced IL-33Δ34-receptor binding and activity. We further find evidence that IL-33 along with mediators of the proteostasis network HSP70, HSP90, and the Chaperonin Containing TCP1 (CCT) complex are dysregulated in human chronic airway disease. This phenomenon is reflected in the differential extracellular vesicle (EV) proteome in bronchial wash from COPD and asthma samples, which could mark disease activity and potentiate IL-33 function. This study confirms proteostasis intermediates, chiefly HSP70, as chaperones for noncanonical IL-33 secretion and activity that may be amenable for therapeutic targeting in the chronic airway diseases COPD and asthma.

This study reveals a mechanism by which heat shock chaperones enhance inflammatory cytokine activity in airway disease pathogenesis. Analysis of lung specimens from patients with chronic obstructive pulmonary diseaes and asthma reveal a global dysregulation of protein quality control pathways that contribute to airway diseases.