Surreal illustration of HAC1 mRNA splicing in a yeast cell

Unlocking Cellular Secrets: How a Serendipitous Discovery Revolutionized Our Understanding of Stress Response

Kai Mendoza in Science & Nature August 2025 • 4 min read.

"Decoding the Unfolded Protein Response (UPR): A Journey from Yeast Genetics to Modern Medicine"

In the vast landscape of scientific research, certain papers transcend the ordinary, becoming cornerstones upon which entire fields are built. These aren't just documents filled with data; they are beacons of insight, illuminating previously uncharted territories of knowledge. One such seminal work is the paper by Cox and Walter, which unveiled the critical role of HAC1 in the unfolded protein response (UPR).

The Unfolded Protein Response (UPR) is a cellular mechanism that gets activated when the endoplasmic reticulum experiences stress, due to an accumulation of unfolded or misfolded proteins. This mechanism is crucial for the survival of cells. This mechanism is crucial for the survival of cells, because of its role to re-establish normal cell functions by stopping protein translation, removing misfolded proteins, and activating the signalling pathways that produce chaperones.

For many researchers, including myself, the Cox and Walter paper was more of a citation than a thorough read—a common pitfall in the fast-paced world of academia. However, upon closer inspection, the elegance and profound implications of their work became strikingly clear. It wasn't just about identifying a new player in cellular stress response; it was a masterclass in experimental design and insightful interpretation.

The Serendipitous Hunt for a Transcription Factor: How Yeast Genetics Unraveled a Cellular Puzzle

Surreal illustration of HAC1 mRNA splicing in a yeast cell

The quest to understand the UPR was akin to searching for a missing piece in a complex puzzle. Scientists knew that the expression of genes like the chaperone protein BiP was upregulated under stress conditions and that the kinase IRE1 played a crucial role. But the identity of the transcription factor responsible for orchestrating this response remained elusive.

Cox and Walter embarked on a journey using a 'sensitive and elegant yeast genetics approach'. Their method involved screening for genes that could activate HIS3 (a gene essential for cell survival) under the control of UPR-responsive elements (UPRE) in yeast cells lacking IRE1. This approach led to the identification of three key genes:

IRE1: Already known for its role in the UPR pathway.
SWI4: A transcription factor involved in general transcriptional machinery.
HAC1: Encoded a novel transcription factor, quickly becoming the focal point of their investigation.

HAC1 emerged as the prime candidate. It not only activated the UPR but also rescued ire1 mutants, binding directly to the UPRE. But a perplexing question remained: how was HAC1 itself regulated? The protein appeared only after UPR induction, despite the continuous presence of its mRNA. This led to the groundbreaking discovery of a shorter HAC1 RNA species appearing under endoplasmic reticulum stress, a result of an unconventional splicing mechanism.

Why This Discovery Still Matters: Lessons in Elegance and the Value of Knowing Your History

The discovery that HAC1 mRNA is spliced upon UPR induction was revolutionary. This splicing event creates a stable protein capable of inducing the UPR. Further, the realization that IRE1 could directly splice HAC1 in the cytosol added another layer of uniqueness to this activation mechanism. This research is more than a historical footnote; it exemplifies how innovative thinking, combined with classical genetics, can unlock fundamental biological processes.

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This article is based on research published under:

DOI-LINK: 10.1038/s41580-018-0043-9, Alternate LINK

Title: An Elegant Upr Discovery

Subject: Cell Biology

Journal: Nature Reviews Molecular Cell Biology

Publisher: Springer Science and Business Media LLC

Authors: Rebecca C. Taylor

Published: 2018-07-20

Everything You Need To Know

What exactly is the Unfolded Protein Response (UPR), and why is it so crucial for cells?

The Unfolded Protein Response (UPR) is a critical cellular mechanism activated when the endoplasmic reticulum is stressed due to an accumulation of unfolded or misfolded proteins. Its main goal is to re-establish normal cell functions by temporarily halting protein translation, clearing misfolded proteins, and activating signaling pathways to produce more chaperones. Without this response, cells would be unable to cope with stress, leading to dysfunction and potentially cell death.

How did the study uncover the role of HAC1 in the Unfolded Protein Response (UPR)?

Cox and Walter's research identified HAC1 as a key transcription factor that activates the UPR. They found that under endoplasmic reticulum stress, HAC1 mRNA undergoes unconventional splicing, leading to the production of a stable and active HAC1 protein. This protein then binds to UPR-responsive elements (UPRE) to upregulate genes involved in the UPR. Their discovery was revolutionary because it revealed a novel mechanism of gene regulation and stress response.

In what way does IRE1 contribute to the activation of HAC1 and the broader Unfolded Protein Response (UPR)?

IRE1 is a kinase that plays a crucial role in the UPR pathway by sensing endoplasmic reticulum stress and initiating signaling cascades. Cox and Walter's work further revealed that IRE1 directly splices HAC1 mRNA in the cytosol under endoplasmic reticulum stress conditions. This unconventional splicing activates HAC1, allowing it to induce the UPR. The discovery that IRE1 could directly splice HAC1 was a groundbreaking finding, adding another layer of uniqueness to this activation mechanism.

What are the broader implications of discovering how HAC1 mRNA splicing is regulated during the Unfolded Protein Response (UPR), especially for human disease?

The discovery of how HAC1 mRNA splicing is regulated by IRE1 during the UPR has had significant implications for understanding cellular stress responses and disease mechanisms. Understanding how the UPR is activated and regulated opens new avenues for therapeutic interventions in diseases where cellular stress plays a significant role. While this research focused on yeast, the fundamental principles often translate to higher organisms, including humans, making it relevant to understanding and treating human diseases. Further research has explored the roles of UPR in neurodegenerative diseases, cancer, and metabolic disorders.

Can you elaborate on the specific yeast genetics approach used to identify HAC1 and its role in the Unfolded Protein Response (UPR)?

Cox and Walter used a yeast genetics approach, screening for genes that could activate HIS3 under the control of UPR-responsive elements (UPRE) in yeast cells lacking IRE1. This method led to the identification of HAC1. This approach allowed them to identify essential components of the UPR pathway and elucidate their functions. This method of screening is a powerful tool for dissecting complex biological pathways.