Cells face various internal and external challenges, from nutrient deprivation to viral infections, which can disrupt their normal functions. To maintain balance and ensure survival, cells have developed adaptive mechanisms. One such mechanism involves Growth Arrest and DNA Damage-inducible protein 34, or GADD34. This protein helps cells respond to stressors and restore cellular equilibrium.
GADD34’s Role in Cellular Stress
When cells encounter stress, particularly within the endoplasmic reticulum (ER) where proteins are folded, a buildup of misfolded proteins can occur. This triggers the Unfolded Protein Response (UPR), a protective mechanism that initially aims to temporarily halt overall protein production to alleviate the ER burden and restore protein homeostasis.
During this response, PERK (protein kinase RNA-like ER kinase) becomes active and phosphorylates eIF2α, a key translation initiation factor. This phosphorylation slows protein synthesis, reducing the load on the stressed ER. If stress persists, however, sustained inhibition of protein synthesis can be detrimental. GADD34 is then induced, often by factors like CHOP, which is activated during prolonged ER stress. GADD34’s expression helps cells recover and resume normal protein production, preventing excessive cell death.
GADD34’s Regulation of Protein Production
GADD34 functions as a regulatory subunit for Protein Phosphatase 1 (PP1), a broadly acting serine/threonine protein phosphatase. Together, GADD34 and PP1 form a complex that specifically targets and dephosphorylates eukaryotic initiation factor 2 alpha (eIF2α). This dephosphorylation is a key step in regulating protein synthesis during stress.
The phosphorylation of eIF2α inhibits global protein synthesis, a response meant to conserve cellular resources under stress. By dephosphorylating eIF2α, GADD34 reverses this inhibition, allowing protein production to gradually resume. This targeted action enables the selective translation of proteins necessary for the cell’s recovery, even as overall protein synthesis normalizes. GADD34 accomplishes this by directly binding to both PP1 and eIF2α, acting as a scaffold to bring the phosphatase to its specific target.
GADD34’s Impact on Health and Disease
GADD34’s involvement extends beyond general cellular stress, playing roles in various health and disease contexts. In viral infections, GADD34 can have a dual impact. Some viruses, like pseudorabies virus (PRV), can induce GADD34 expression to promote eIF2α dephosphorylation, thereby maintaining protein synthesis and facilitating their own replication. Conversely, GADD34 can also suppress viral replication, as seen with vesicular stomatitis virus (VSV), by inhibiting the mTOR signaling pathway, which reduces viral protein synthesis. The SARS-CoV-2 nucleocapsid protein, for instance, has been shown to inhibit GADD34 expression, which can dampen the host’s innate immune response and promote viral replication.
In the context of cancer, GADD34’s role can be complex and context-dependent. The proto-oncogene c-myc, often highly expressed in many human breast cancers, can suppress GADD34 expression. This suppression suggests GADD34 might be an important target in cancer development, as GADD34 can induce apoptosis (programmed cell death) in cancer cells. However, GADD34 can also protect liver cancer cells from certain types of apoptosis by stabilizing pro-survival proteins, highlighting its varied effects depending on the cancer type and specific stimuli.
GADD34 is also implicated in neurodegenerative diseases, where ER stress and protein misfolding are common features. In Alzheimer’s disease (AD), GADD34 levels are increased in the brains of affected individuals and mouse models. The accumulation of amyloid-beta (Aβ), a hallmark of AD, can induce GADD34 expression, and reducing GADD34 has been shown to rescue cells from Aβ-induced apoptosis. In Parkinson’s disease (PD), GADD34 has been identified as a potential therapeutic target, with some studies exploring the inhibition of GADD34 function as a strategy to delay neurodegeneration and promote cell survival.
Beyond these conditions, GADD34 has been linked to metabolic disorders. Mice lacking GADD34 can show increased susceptibility to obesity, fatty liver, and insulin resistance when fed a high-fat diet. This suggests GADD34 contributes to metabolic regulation, although the precise mechanisms are still being explored. These diverse roles underscore GADD34’s broad influence on cellular health and its potential as a target for various therapeutic interventions.