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](/entities/unfolded-protein-response) (UPR).[@ham2014] HIP2 was initially identified as a huntingtin-interacting protein through yeast two-hybrid screening, suggesting a potential link to Huntington's disease pathology.[@kalchman1997]
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](/entities/unfolded-protein-response) (UPR).[@ham2014] HIP2 was initially identified as a huntingtin-interacting protein through yeast two-hybrid screening, suggesting a potential link to Huntington's disease pathology.[@kalchman1997]
Structure and Domains
HIP2 contains:
N-terminal ER-targeting signal sequence — directs the protein to the ER lumen
FIC (Filamentation Induced by cAMP) domain — contains the conserved HxFx(D/E) motif responsible for AMPylation activity
Transmembrane domain — anchors the protein to the ER membrane with the catalytic domain in the ER lumen
The FIC domain catalyzes the transfer of AMP from ATP to target proteins (AMPylation), a reversible post-translational modification that regulates chaperone function.[@preissler2015]
Normal Function
ER Chaperone Regulation
HIP2/FICD AMPylates the ER chaperone BiP (GRP78/HSPA5) at threonine-518, which:
Inactivates BiP during resting conditions — prevents unnecessary UPR activation
Releases BiP upon ER stress — allows BiP to bind unfolded proteins and initiate the UPR
Maintains ER homeostasis — acts as a "rheostat" for protein quality control
This dual function makes HIP2 both an AMPylase and de-AMPylase, providing bidirectional control over BiP activity.[@perera2019]
Protein Quality Control
Monitors the folding status of nascent polypeptides in the ER
Regulates the balance between protein folding and degradation
Prevents chronic UPR activation that could lead to [apoptosis](/entities/apoptosis)
Role in Neurodegeneration
Huntington's Disease
HIP2 interacts directly with [huntingtin protein](/proteins/huntingtin), and this interaction may be altered by polyglutamine expansion:[@kalchman1997]
Huntingtin binding — HIP2 binds to the N-terminal region of huntingtin
Proteasome regulation — HIP2 also interacts with the 26S proteasome, potentially linking HD pathology to impaired protein degradation
ER stress in HD — Expanded huntingtin causes ER stress, and HIP2 dysfunction may exacerbate this
ER Stress-Related Neurodegeneration
Given its role in UPR regulation, HIP2 dysfunction may contribute to:[@hetz2017]
Alzheimer's disease — Chronic ER stress contributes to [Aβ](/proteins/amyloid-beta) toxicity and [tau](/proteins/tau) pathology
Parkinson's disease — [α-Synuclein](/proteins/alpha-synuclein) aggregation induces ER stress
ALS/FTD — [TDP-43](/mechanisms/tdp-43-proteinopathy) and FUS mislocalization cause ER stress
Proteostasis Network
HIP2 represents a critical node in the cellular proteostasis network:[@sanyal2022]
Chaperone modulation — Regulates the primary ER chaperone BiP
UPR tuning — Controls sensitivity to ER stress signals
Cross-talk with [autophagy](/entities/autophagy) — ER stress responses intersect with autophagic degradation
Therapeutic Targeting
Targeting ER Stress
Modulation of HIP2 activity could provide therapeutic benefits:
Inhibitors — Small molecule FICD inhibitors could amplify UPR signaling during acute stress
Activators — Enhancement of AMPylation activity might protect against chronic UPR activation
Challenges
Specificity — The FIC domain is conserved across multiple protein families
Dual activity — HIP2 has both AMPylase and de-AMPylase functions
ER targeting — Drug delivery to the ER lumen is challenging
Protein Interactions
| Partner | Function | Disease Relevance | |---------|----------|-------------------| | [Huntingtin](/proteins/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 (2014)](https://doi.org/10.1016/j.molcel.2014.09.019)
[Kalchman MA, et al, HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain (1997)](https://pubmed.ncbi.nlm.nih.gov/9321401/)
[Preissler S, et al, FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP (2015)](https://doi.org/10.1038/nsmb.2994)
[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 (2019)](https://doi.org/10.1074/jbc.RA119.010689)
[Hetz C, Saxena S, The ER stress and the unfolded protein response: At the intersection of neurodegeneration and metabolism (2017)](https://doi.org/10.1016/j.neuron.2017.07.025)
[Sanyal A, et al, Mechanisms of ER stress in neurodegenerative diseases (2022)](https://doi.org/10.1016/j.conb.2022.102541)