ASBMB Annual Meeting

Arrieta follows the heart to find a protein function

Meet a JBC Herbert Tabor Early Career Investigator Award winner
Leia Dwyer
March 8, 2021

When Adrian Arrieta started undergraduate studies in molecular toxicology at the University of California, Berkeley, he anticipated a career in drug development and pharmacology. However, a comparison of normal and cancerous human karyotypes in a genetics class sparked his interest in molecular mechanisms of disease.

Arrieta-Adrian-445x425.jpg
Adrian Arrieta

Arrieta joined Christopher Glembotski's lab at San Diego State University for his doctoral research, working on the premise that a tumor microenvironment has a high degree of protein misfolding and shares characteristics with a heart undergoing ischemia. Upregulated genes in cancer cells might provide a clue to which proteins in the heart respond protectively to stress.

Arrieta and his team's research was published in the Journal of Biological Chemistry. A collaborative environment was key to his success, he said; the lab had to develop new assays and techniques. "We really had to start from the ground up," he said. "Everyone in the author block did something to make this happen."

Arrieta is now a postdoc at the David Geffen School of Medicine at UCLA in Thomas Vondriska's lab. Arrieta met Vondriska during a talk on Arrieta's paper at a conference on cardiac regulatory mechanisms. The two were intrigued by each other's research, and Arrieta is now investigating protein quality control in the context of chromatin dynamics in the heart.

He's excited to be back in LA, where he grew up, because he can be with his family and enjoy home-cooked meals. "My mother told me that when I was little, I told her I was going to work at UCLA," he said. "Now, here I am — full circle."

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.

Leia Dwyer

Leia Dwyer is a Boston-area biotech and pharmaceutical industry professional.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in People

People highlights or most popular articles

Spriggs to start lab; Cejka joins EMBO
Member News

Spriggs to start lab; Cejka joins EMBO

Aug. 2, 2021

Awards, promotions, milestones and more. Find out what's going on in the lives of ASBMB members.

In memoriam: Gerhard Meissner
In Memoriam

In memoriam: Gerhard Meissner

Aug. 2, 2021

He was a professor at the University of North Carolina at Chapel Hill and an ASBMB member for more than 40 years.

Meet Stephanie Moon
Observance

Meet Stephanie Moon

Aug. 2, 2021

She studies messenger RNA regulation at the University of Michigan in Ann Arbor.

Journal of Biological Chemistry names new editor-in-chief
Journal News

Journal of Biological Chemistry names new editor-in-chief

July 30, 2021

Alex Toker, professor of pathology at the Beth Israel Deaconess Medical Center and Harvard Medical School, will begin his term Oct. 1.

Conaway named vice provost; Emr wins Shaw Prize; remembering Hartley
Member News

Conaway named vice provost; Emr wins Shaw Prize; remembering Hartley

July 26, 2021

Awards, promotions, milestones and more. Find out what's going on in the lives of ASBMB members.

Remembering Turk and Yamamoto
In Memoriam

Remembering Turk and Yamamoto

July 19, 2021

We look back on the lives of a mass spectrometry pioneer and member of the JBC editorial board and a researcher focused on enzymology and the biochemistry of lipids involved in inflammation.