Blocking a Critical Enzyme Helps to Mitigate Diseases associated with Protein Folding and Lipid Stress

These images show a reduction in the number of macrophages infiltrating atherosclerotic plaques (in green) in animals treated with the IRE1 inhibitor. Credit: Image courtesy of University of California – Santa Barbara

Proteins begin life as long strings of amino acids that must fold into the 3D shape prescribed for their biological function. When proteins don’t fold as expected the cells activate stress responses meant to mitigate the problem. But severe or prolonged stress produces an acute response: Cell death is triggered to protect the organism.

Sustained activation of one such reaction – the unfolded protein response, or UPR – has been implicated in a number of diseases. Seeking to illuminate a piece of this biological puzzle, an international team of scientists, including UC Santa Barbara cell biologist Diego Acosta-Alvear, examined the role of a central UPR component, a stress sensor protein called IRE1 (inositol-requiring enzyme 1), in atherosclerosis.

The researchers found that blocking IRE1 with a small molecule prevented the progression of atherosclerosis in mice. “A healthy cell has one type of stress response network wiring and it’s likely that a diseased cell accommodates that wiring to survive,” said Assistant Professor Acosta-Alvear, UCSB’s Department of Molecular, Cellular and Developmental Biology. “Stress response networks control the life vs. death decision in cells, and since a diseased cell is nowhere near its comfort zone, rewiring its stress responses allows it to avoid or delay cell death even when conditions are adverse.”

The UPR is triggered when the normal functions of the endoplasmic reticulum are compromised. Though the UPR usually promotes healthy endoplasmic reticulum function, sustained UPR activation sometimes results in diseases such as atherosclerosis among other conditions. Endoplasmic reticulum stress is triggered not only by protein-folding problems, but also by fatty acids, explained Acosta-Alvear. Fat-induced stress and metabolic overload of the endoplasmic reticulum can alter its function, triggering chronic inflammation, which plays an important role in the development of atherosclerosis.

In this research, the scientists disturbed endoplasmic reticulum function by introducing saturated fatty acids into cells to induce lipotoxic stress. This in turn activated the UPR and IRE1. Active IRE1 relays the protein-folding stress information to the cell nucleus by controlling the production of a very potent transcription activator, XBP1 (X-box binding protein-1). Transcription activators are proteins involved in transcribing DNA into RNA. The investigators’ analyses demonstrated that XBP1 was responsible for turning on pro-atherogenic genes. They then treated mice with a compound that blocked IRE1.

“The end result was that if the transcription factor was not produced, the pro-atherogenic genes were not turned on, which mitigated the progression of the disease,” Acosta-Alvear said. “This research is a proof-of-concept study showing that blocking this single critical enzyme delivers a desirable therapeutic benefit. It’s a first step in mechanistically understanding how cellular stress responses are wired in specific contexts.” http://www.news.ucsb.edu/2017/017635/origami-cell