Activating transcription factor 6 (ATF6) is a protein that functions as a cellular stress sensor. It is situated within the membrane of a cellular structure called the endoplasmic reticulum (ER). The ER is a network of membranes inside our cells that has several jobs, but a primary one is to serve as the cell’s main protein folding factory. Here, newly made proteins are folded into the specific three-dimensional shapes they need to function correctly.
ATF6 constantly monitors the health of this protein-folding environment. In a healthy cell, protein production and folding proceed smoothly. ATF6 remains in an inactive state, embedded in the ER membrane. It is an integral part of the cell’s quality control system, standing by to detect any disruptions in the protein assembly line.
The Unfolded Protein Response and ATF6
When the endoplasmic reticulum experiences disruptions, it can lead to a condition known as “ER stress.” This state occurs when there is an imbalance between the number of proteins entering the ER and the organelle’s capacity to fold them. Factors like nutrient deprivation, viral infections, or genetic mutations can cause newly synthesized proteins to fail to fold correctly, leading to an accumulation of unfolded or misfolded proteins. This buildup is toxic to the cell.
To manage this stress, cells activate a quality control system called the Unfolded Protein Response (UPR). The UPR is a set of signaling pathways designed to restore balance, or homeostasis, within the ER. Its goals are to halt the production of new proteins temporarily, increase the machinery needed to fold proteins correctly, and clear out the problematic misfolded proteins.
The UPR is initiated by three main sensor proteins embedded in the ER membrane that detect the accumulation of unfolded proteins. ATF6 is one of these primary sensors, alongside two others named Inositol-Requiring Enzyme 1 (IRE1) and Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK). When unfolded proteins build up, they attract chaperone proteins, like GRP78/BiP, pulling them away from the sensors. This unbinding event is the signal that triggers the activation of ATF6 and the other UPR pathways.
The ATF6 Activation Mechanism
Under normal, non-stressful conditions, ATF6 is held inactive in the ER membrane through its association with a chaperone protein called GRP78, also known as BiP. This chaperone binds to the part of ATF6 that resides within the ER lumen—the space inside the ER—preventing it from moving.
When ER stress occurs, the accumulating unfolded proteins require the assistance of GRP78 to help them fold. GRP78 releases ATF6 to attend to these unfolded proteins. Once released, ATF6 is packaged into transport vesicles that bud off from the ER membrane. These vesicles then travel and fuse with the Golgi apparatus, another organelle that acts as a cellular post office, modifying and sorting proteins.
Inside the Golgi apparatus, ATF6 undergoes a two-step cutting process by enzymes called proteases. First, one enzyme cleaves the ATF6 protein. This initial cut sets the stage for a second enzyme to make another cut within the part of the ATF6 protein that spans the Golgi membrane. This second cleavage liberates the active portion of ATF6.
The liberated piece is a smaller protein fragment. This fragment is now free in the cell’s cytoplasm. From there, it moves into the cell’s nucleus, which houses the cell’s genetic material, DNA. Inside the nucleus, this active ATF6 fragment can perform its primary function as a transcription factor.
Cellular Outcomes of ATF6 Signaling
Once the active fragment of ATF6 arrives in the nucleus, it functions as a transcription factor. This means it binds to specific sequences of DNA, known as promoter regions, to switch on or increase the expression of a targeted set of genes. The collection of genes activated by ATF6 is specifically aimed at alleviating the stress within the endoplasmic reticulum and restoring its protein-folding capacity.
A primary group of genes turned on by ATF6 codes for ER chaperones. These are proteins, including the very GRP78/BiP that initially held ATF6 inactive, whose job is to assist in the proper folding of other proteins. By increasing the number of chaperones, the cell boosts its capacity to correctly fold the backlog of unfolded proteins, directly addressing the root cause of the ER stress.
Another set of genes activated by ATF6 is involved in a process called ER-associated degradation (ERAD). This pathway serves as a disposal system for misfolded proteins that are beyond repair. If a protein cannot be folded correctly even with the help of chaperones, the ERAD machinery targets it for removal from the ER. The protein is then tagged and transported to the proteasome, the cell’s garbage disposal, where it is broken down.
ATF6 also promotes the synthesis of lipids, which are the building blocks of cellular membranes. By upregulating genes involved in lipid production, the cell can physically expand the size of the endoplasmic reticulum. A larger ER provides more surface area and volume, diluting the concentration of misfolded proteins and providing more space for the folding machinery to work.
Implications in Disease and Therapy
The proper functioning of the ATF6 pathway is linked to human health, and its disruption is implicated in a wide range of diseases. Because protein folding is fundamental to cellular activities, problems with the ATF6 stress response can have far-reaching consequences. Its role is prominent in conditions characterized by high levels of protein production or the accumulation of misfolded proteins.
In cancer, ATF6 has a complex, dual role. In some scenarios, cancer cells hijack the ATF6 pathway to survive the stressful conditions of a tumor environment. By activating the UPR, cancer cells can manage ER stress and continue to proliferate, making ATF6 a potential target for therapies. Conversely, chronic ER stress can trigger ATF6 to activate genes that promote cell death, or apoptosis, acting as a tumor suppressor.
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s, are protein-misfolding disorders. In these conditions, specific proteins misfold and aggregate in neurons, leading to cellular dysfunction and death. The ATF6 pathway is activated in response to this protein toxicity, but its capacity to resolve the stress can be overwhelmed over time. Enhancing ATF6 activity is being explored as a therapeutic strategy to help clear these toxic protein aggregates.
The ATF6 pathway is also involved in metabolic disorders like diabetes and fatty liver disease, where cells are under constant stress from high levels of glucose or lipids. It also plays a part in damage from ischemia, a condition where tissues are deprived of oxygen-rich blood. Loss-of-function mutations in the ATF6 gene have been linked to specific genetic disorders, such as certain forms of congenital vision and hearing loss, highlighting its importance in sensory cells.