GADD153, also known as C/EBP homologous protein (CHOP) or DNA damage-inducible transcript 3 (DDIT3), is a protein that plays a role in how cells respond to various internal and external challenges. It is a transcription factor, meaning it helps control which genes are turned on or off within a cell. This protein is typically present at low levels but becomes significantly more abundant when cells experience stress, helping to maintain cellular stability and health.
Responding to Cellular Stress
GADD153 is primarily involved in the “unfolded protein response” (UPR), a mechanism initiated when misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER). The ER is a network of membranes within the cell where proteins are synthesized, folded, and modified. When the ER’s ability to fold proteins is overwhelmed, it creates a state known as ER stress.
Cells detect this stress through specific sensors, including PERK, IRE1, and ATF6, located in the ER membrane. Activation of these sensors initiates a signaling cascade that restores balance within the ER. For instance, PERK activation leads to a reduction in protein synthesis, easing the load on the ER, and promoting the expression of specific genes involved in stress relief.
GADD153 is strongly activated during this UPR, particularly through the PERK-eIF2α-ATF4 pathway. Its induction helps the cell adapt by increasing the production of ER chaperones, proteins that assist proper protein folding. This adaptive response clears the backlog of misfolded proteins and re-establishes the ER’s normal function.
Directing Cell Survival or Demise
While GADD153 initially helps cells cope with stress, its sustained or intense activation can shift the cell towards programmed cell death (apoptosis). It pushes the cell towards self-destruction if the stress is too severe or prolonged. This controlled demise prevents damaged cells from harming the organism.
One way GADD153 promotes apoptosis is by influencing the balance of pro-apoptotic and anti-apoptotic proteins in the BCL2 family. GADD153 can downregulate the expression of anti-apoptotic proteins like BCL2, which protect the cell from death. Simultaneously, it can upregulate pro-apoptotic proteins such as BIM, BAK, and BAX, which contribute to the apoptotic cascade.
GADD153 also contributes to apoptosis by depleting cellular glutathione, a molecule protecting cells from oxidative damage. This depletion leads to an increase in reactive oxygen species, further stressing the cell and promoting its death. Its pro-apoptotic effects are also linked to inducing TRIB3, a pseudokinase that inhibits survival pathways.
Role in Various Health Conditions
Dysregulation of GADD153 activity is implicated in the progression of various diseases. For example, GADD153 has been linked to several types of cancer. In some cancers, its sustained activation can promote tumor cell death, making it a potential therapeutic target.
GADD153 also plays a role in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In these conditions, chronic ER stress and subsequent GADD153 activation contribute to neuronal cell death, a hallmark of these diseases. Understanding how GADD153 contributes to neuronal loss may offer new treatment avenues.
Furthermore, GADD153 is involved in metabolic diseases like diabetes. In diabetes, ER stress in insulin-producing pancreatic beta cells can lead to their dysfunction and death, and GADD153 significantly contributes to this process. Insights into GADD153’s actions in these diverse health conditions can deepen understanding of disease mechanisms and lead to new therapeutic strategies.