Projects
Cell and molecular biology of Regulated IRE1α-Mediated Decay (RIDD) in epithelial fate transitions
IRE1α is an endoplasmic reticulum (ER) transmembrane protein containing a luminal domain that is responsive to protein-folding stress (ER stress). IRE1α is ancient and its functions are conserved throughout eukaryotes. Upon stress, IRE1α kinase domains self-associate and trans-autophosphorylate, which activates the RNase domain to cleave the mRNA of the XBP1 transcription factor and initiate its alternative splicing. Spliced XBP1 upregulates factors that promote ER protein folding including chaperones and oxidoreductases. Under severe ER stress, IRE1α degrades a plethora of mRNAs localizing to the ER membrane and select micro-RNAs in a process dubbed Regulated IRE1α-Dependent Decay (RIDD).
Though protein folding homeostasis was IRE1α's ancestral function, we think it evolved to take on more complex roles as multicellular organisms developed. In particular, our work on epithlelial transition states in fibrosis suggests that RIDD regulates epithelial plasticity by degrading mRNAs encoding genes important to maintaining cellular identity. These genes include some that are not predicted to be translated at the ER membrane. We are exploring the idea that enzyme and substrate only come together during crisis: that cell state and identity causes recruitment of select mRNAs to IRE1α on the cytosolic face of the ER.
Fate and function of epithelial transitional states in pulmonary fibrosis
Idiopathic pulmononary fibrosis (IPF), the most common form of lung fibrosis, is a disease of progressive respiratory failure with limited treatment options. A new paradigm recently emerged in the biology of lung fibrosis: in the course of repairing the lung, facultative stem cells enter "transitional" states that can actually be pathological. On one hand, transitional states can successfully differentiate into newly regenerated lung tissue, but on the other hand, failure to differentiate can instead nucleate fibrotic disease.
Using single-cell sequencing, we have found that cells enter a particular transitional state that is uniquely found in models of fibrosis and human fibrotic lungs. We hypothesize that fibrotic lung injury causes lung epithelial stem cells to detour into a dead-end pathologic state, where they are unable to differentiate into new alveolar epithelial cells. We are using new genetic tracing tools to follow the fates of cells in the fibrotic state, and new spatial transcriptomic platforms to characterize their interactions with other cells in the fibrotic niche.
The niche signals and cell-intrinsic pathways that drive cells into the fibrotic dead-end state are incompletely understood. Cells in the state exhibit features of senescence and cellular stress, including a signature of unfolded protein response (UPR) and IRE1α activation. Using genetic tools and unique small-molecule modulators of the IRE1α kinase, we have shown that inhibiting IRE1α reduces fibrosis and promotes successful differentiation. We using a new generation of IRE1α modulators to understand the molecular mechanisms of how IRE1α regulates the fibrotic state. Our goal is to use small molecules to modulate IRE1α and other signals/pathways and get cells back onto a regenerative track to repair the lung.
Regulation of goblet cell metaplasia in asthma and other muco-obstructive diseases
Mucus hypersecretion causes symptoms and reduces lung function in human asthma and other lung diseases, including COPD and chronic rhinosinusitis. Despite advances in targeted therapies to reduce inflammation in asthma, there are no therapies that directly target mucus hypersecretion.
In human airways, basal cells differentiate into mucin-producing goblet cells in response to allergic inflammatory signals. In collaboration with the UCSF Asthma and Allergic Diseases Cooperative Research Center, we have found that the unfolded protein response (UPR) and IRE1α are activated during differentiation. Using genetic tools and small-molecule modulators of the IRE1α kinase, we have shown that inhibiting IRE1α reduces goblet cell metaplasia in vivo and in air-liquid interface culture. We using a new generation of IRE1α modulators to understand the molecular mechanisms of how IRE1α regulates goblet cell maturation. Our goal is to use small molecules to inhibit IRE1α and get airway epithelial cells to "step back from the brink" of the goblet cell fate, and thus reduce mucus and symptom burden in asthma.
Epithelial-immune-stromal topography in human lung disease
In end-stage lung injury and fibrosis, a complex web of interactions takes place between the epithelium, matrix-depositing fibroblasts, and dysregulated immune cells to produce the tissue- and organ-level pathology that patients experience as progressive breathlessness and respiratory failure. With support from an American Lung Association Hastings Innovation Award and the UCSF ImmunoX program, we designed spatial transcriptomic probe panels optimized for human lung disease, and we have now spatially mapped more than 5 million cells from more than 120 human subjects with a variety of lung diseases. We use these maps to identify recurring multicellular niches, including fibroblastic foci, aberrant COL15A1+ endothelium, extrafollicular plasma cell zones, and lymphoid aggregates that range from loose clusters to organized tertiary lymphoid structures (TLS). Some of these structures have been recognized by pathologists for decades, but their cellular composition and the signals they exchange have been difficult to study in intact human tissue. We are asking how these "niches" form, how they differ across diseases and between patients, and how they communicate with the epithelium around them. Our overarching goal is to identify the niche signals that push epithelial cells into dysplastic, pathological states, so that we can design therapies that interrupt fibrotic remodeling while preserving the lung’s capacity for repair.
Publications
Highlights
Auyeung VC, Steinberg TL, Olivier A, Suzuki L, Moreno ME, Khan IS, Downey MS, Thamsen M, Guo L, Maly DJ, Backes BJ, Sheppard D, Papa FR. Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice. J Clin Invest. 2025 10 15; 135(20). . PMID: 41090357; PMCID: PMC12520674.
IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2022 Apr 1;322(4):L564-L580. doi: 10.1152/ajplung.00408.2021. Epub 2022 Feb 16. PubMed PMID: 35170357; PubMed Central PMCID: PMC8957349.