Week 3- The Pathway that Bridges the Two: Introducing mTORC-1
Anita M -
The past few days consisted of signing my DCC form and completing online lab training. In the meantime, I am still reading through human physiology and pathology, as well as expanding my knowledge on GRASP55 (the protein of interest for my project). Here’s a more detailed look at the link between GRASP55 and ATF6:
When someone experiences a heart attack, ischemia, or hypoxia (basically any lack of oxygen to heart tissues), some heart tissue dies. The cells surrounding the dead tissue become stressed. More specifically, their ER becomes stressed and starts to misfold/not fold proteins.
ER stress inhibits a pathway called the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is largely involved in maintaining cellular metabolism and basic cellular functions (such as growth, autophagy, etc.). When mTORC1 is inhibited under stressful conditions, GRASP55 relocalizes and becomes involved in unconventional protein secretion. As opposed to conventional protein secretion (Ribosome–> Rough ER–> Golgi Apparatus), unconventional protein secretion is protein secretion that bypasses the Golgi Apparatus (basically, the proteins don’t get “packaged” and leave the cell in vesicles that stay intact).
Under normal stress-free conditions, mTORC1 is activated and GRASP55 remains as a structure of the Golgi Apparatus and does not become a part of unconventional protein secretion. Proteins secreted unconventionally are found in the plasma membrane of the cell and the extracellular matrix (ECM), and some secreted ECM proteins have been found to play vital roles in various physiological conditions such as cancer, inflammation, angiogenesis (development of blood vessels), and neurological diseases.
ER Stress also leads to activation of ATF6, which activates the UPR and attempts to bring the cell back to homeostasis. Furthermore, ATF6 also has the ability to activate mTORC1. Remember that when mTORC1 is activated, GRASP55 is “turned off” and unconventional protein secretion doesn’t occur. So therein lies the question: why doesn’t ATF6 activate mTORC1 under stressful conditions? And how does inhibition of mTORC1 and activation of GRASP55 effect ATF6?
We are trying to investigate the link between GRASP55 and ATF6 and since mTORC1 is a pathway that links the two, it is important to understand the role mTORC1 plays in each pathway. Hopefully by discovering if/how GRASP55 and ATF6 are related, we can also find answers to how the role of mTORC1 is altered for patients who have experienced a heart attack.
Starting next week, I will began experiments on HEK293 cells to further investigate the relationship between GRASP55 and ATF6 for patients who have experienced heart attacks.
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