Major step found in cellular response to stress caused by pathological insult

March 6, 2018, The Wistar Institute
Credit: The Wistar Institute

A new study conducted by researchers at The Wistar Institute revealed how a key protein residing in the endoplasmic reticulum (ER) helps cells respond to stress. This process is especially important for B cells to respond to severe stress conditions and their ability to produce antibodies. The research was published online in the Journal of Cell Biology.

The ER is a cellular structure where protein production, folding and assembly occur. It harbors complex mechanisms to supervise these processes and respond to the caused by the accumulation of misfolded proteins resulting from a number of pathological and pharmacological causes.

IRE1 is a that senses ER stress and responds by activating two cascades of cellular events. IRE1 regulates the maturation of the XBP1 mRNA to produce the functional XBP1 transcription factor, which in turn bolsters the expression of target genes encoding for that resolve the accumulation of misfolded proteins. IRE1 can also engage a mechanism called regulated IRE1-dependent decay (RIDD) by cleaving a subset of messenger RNAs to reduce the load of proteins coming into the ER until the crisis is resolved. IRE1 function is especially critical in B cells since the ER plays a central role in the biogenesis of antibodies. However, the molecular mechanism that regulates the RIDD function of IRE1 remained unclear.

In the study, Chih-Chi Andrew Hu, Ph.D., associate professor in Wistar's Immunology, Microenvironment & Metastasis Program, and colleagues characterized a novel phosphorylation that regulates IRE1 to perform RIDD in response to specific ER stress conditions.

"Our results showed that this phosphorylation is critical for IRE1 function during production of antibodies in response to immunization," said Chih-Hang Anthony Tang, Ph.D., a staff scientist in the Hu Lab and first author of the study.

The researchers specifically examined the status of the IRE1 in XBP1-deficients cells and discovered the phosphorylation at Ser729 of IRE1. They then extensively characterized the function of this phosphorylation by creating an antibody that specifically recognizes IRE1 when phosphorylated in that particular site. They also generated a knock-in mouse model that expresses a mutant IRE1 that cannot undergo phosphorylation to study the consequences of its absence.

"Deepening our understanding of a fundamental player in the ER stress response will provide us with useful tools to interrogate the biology of ER stress response in human pathological conditions, including metabolic, neurodegenerative, immune disease and cancer," Hu said.

Explore further: Pathway's power to boost, halt tumors may be promising cancer therapy target

Related Stories

Pathway's power to boost, halt tumors may be promising cancer therapy target

August 29, 2017
A protein, called inositol-requiring enzyme 1—IRE1—may serve as a key driver in a series of molecular interactions that can both promote and, paradoxically, inhibit tumors in certain types of cancers, such as non-melanoma ...

Clarifying the role of CHOP/GADD153 in cell death

May 13, 2016
The results of preclinical studies by investigators at the Medical University of South Carolina (MUSC) reported in the May 2016 issue of Nature Communications demonstrate that CHOP/GADD153-dependent apoptosis reflects expression ...

Newly identified molecular mechanism plays role in type 2 diabetes development

July 30, 2015
New research from Harvard T.H. Chan School of Public Health describes a molecular mechanism that helps explain how obesity-related inflammation can lead to type 2 diabetes. The findings describe a surprising connection between ...

Helping the heart to cope with stress

February 26, 2018
A new Junior Research Group at the Institute for Cardiovascular Prevention will focus on metabolic adaption of heart muscle cells to find new therapies for combating heart disease.

Recommended for you

Calorie restriction trial in humans suggests benefits for age-related disease

March 22, 2018
One of the first studies to explore the effects of calorie restriction on humans showed that cutting caloric intake by 15% for 2 years slowed aging and metabolism and protected against age-related disease. The study, which ...

Boosting enzyme may help improve blood flow, fitness in elderly

March 22, 2018
As people age, their blood-vessel density and blood flow decrease, which is why it's harder to maintain muscle mass after 40 and endurance in the later decades, even with exercise. This vascular decline is also one of the ...

Scientists pinpoint cause of vascular aging in mice

March 22, 2018
We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality?

Sulfur amino acid restriction diet triggers new blood vessel formation in mice

March 22, 2018
Putting mice on a diet containing low amounts of the essential amino acid methionine triggered the formation of new blood vessels in skeletal muscle, according to a new study from Harvard T.H. Chan School of Public Health. ...

Gradual release of immunotherapy at site of tumor surgery prevents tumors from returning

March 21, 2018
A new study by Dana-Farber Cancer Institute scientists suggests it may be possible to prevent tumors from recurring and to eradicate metastatic growths by implanting a gel containing immunotherapy during surgical removal ...

Cold can activate body's 'good' fat at a cellular level, study finds

March 21, 2018
Lower temperatures can activate the body's 'good' fat formation at a cellular level, a new study led by academics at The University of Nottingham has found.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.