HIP2 (Huntingtin Interacting Protein 2), also known as HYPE (Huntingtin yeast partner E) or FICD (FIC domain protein adenylyltransferase), is an endoplasmic reticulum (ER)-resident enzyme that catalyzes AMPylation (adenylylation) of ER chaperones, playing a critical role in protein quality control and the unfolded protein response (UPR).[1] HIP2 was initially identified as a huntingtin-interacting protein through yeast two-hybrid screening, suggesting a potential link to Huntington's disease pathology.[2]
HIP2 contains:
The FIC domain catalyzes the transfer of AMP from ATP to target proteins (AMPylation), a reversible post-translational modification that regulates chaperone function.[3]
HIP2/FICD AMPylates the ER chaperone BiP (GRP78/HSPA5) at threonine-518, which:
This dual function makes HIP2 both an AMPylase and de-AMPylase, providing bidirectional control over BiP activity.[4]
HIP2 interacts directly with huntingtin protein, and this interaction may be altered by polyglutamine expansion:[2:1]
Given its role in UPR regulation, HIP2 dysfunction may contribute to:[5]
HIP2 represents a critical node in the cellular proteostasis network:[6]
Modulation of HIP2 activity could provide therapeutic benefits:
| Partner | Function | Disease Relevance |
|---|---|---|
| Huntingtin | PolyQ protein | Huntington's disease |
| BiP/HSPA5 | ER chaperone | Multiple neurodegenerative diseases |
| 26S Proteasome | Protein degradation | Proteostasis disorders |
| ATF6 | UPR sensor | ER stress response |
Ham H, et al. FICD acts as a dual-function AMPylase/de-AMPylase in BiP regulation. Molecular Cell. 2014. ↩︎
Kalchman MA, et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nature Genetics. 1997. ↩︎ ↩︎
Preissler S, et al. FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP. Nature Structural & Molecular Biology. 2015. ↩︎
Perera LA, et al. Intrinsic AMPylation and de-AMPylation by a single FIC domain enzyme is fine-tuned by the presence of a tetratricopeptide repeat domain. Journal of Biological Chemistry. 2019. ↩︎
Hetz C, Saxena S. The ER stress and the unfolded protein response: At the intersection of neurodegeneration and metabolism. Neuron. 2017. ↩︎
Sanyal A, et al. Mechanisms of ER stress in neurodegenerative diseases. Current Opinion in Neurobiology. 2022. ↩︎