Arrieta follows the heart to find a protein function

Finding the function of an ER-resident chaperone in the heart

After cardiac ischemia, reperfusion injury can occur when blood returns to the tissue. Ischemia/reperfusion, or I/R, disrupts protein folding and post-translational modification in the endoplasmic reticulum, causing loss of protein function and activating the ER stress response.

Mesencephalic astrocyte-derived neurotrophic factor, or MANF, is part of a gene program regulated by an ER stress response transcription factor. For more than a decade, researchers knew that MANF was upregulated in models of heart disease but didn't know its exact function. MANF bears no structural similarity to other ER proteins, and this got Adrian Arrieta wondering. "If it doesn't look like anything else that's been studied in the heart or any other tissue, it must be doing something really unique," he said. "That was the draw."

Arrieta and his colleagues in the Glembotski lab at San Diego State did experiments spanning techniques and specialties to deduce MANF function. They developed a knockdown mouse model to study MANF in both cells and mouse hearts. Lack of MANF expression in the heart increases cardiac damage during I/R injury, they found, and restoring MANF expression can reverse those effects. MANF also improved ER proteostasis during reperfusion injury.

The team found that MANF acts in response to reductive, not oxidative, stress during reperfusion injury and isolated its function as an ER-resident chaperone. Finally, by generating and studying a mutant version of the protein, Arrieta determined that conserved cysteine residues in the MANF molecule are required for its chaperone function. MANF's lack of structural homology remains a question for future research.