Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CHIP

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101582

Synonyms

 STUB1

Historical Background

Maintaining the integrity of the proteome is a tedious task. Nascent, misfolded, or denatured polypeptides are captured by molecular chaperones which try to fold them into their native conformations. Upon failure these polypeptides are channeled for degradation in a ubiquitin dependent manner, suggesting the presence of a link between chaperones and the 26S proteasome. An important feature of many chaperone-interacting proteins is the presence of tetratricopeptide repeats (TPR) which are protein-protein interacting motifs. In an attempt to identify novel TPR containing proteins, a cDNA fragment corresponding to nucleotides 721–1150 of CyP-40 (cytochrome P-40) was radiolabeled with [α-32P]dCTP and used to screen a phage library of human heart cDNA. Carboxy terminus of HSP70 Interacting Protein (CHIP) was identified through this screen. The gene for CHIP encodes for a 34.5 kDa protein which is well-conserved with an amino acid sequence similarity of ~98% with mouse. It was found to be highly expressed in tissues with a large proportion of terminally differentiated, nonproliferating cells and high levels of metabolic activity such as skeletal muscle, heart, and brain. Further, observations that ~20% of CHIP null (CHIP−/−) mice dies at embryonic stages and 100% fails to survive thermal stress provided initial hints toward a possible role of CHIP in protein turnover. CHIP was identified as a TPR-containing protein that inhibited forward cycle of chaperones (Fig. 1). However, the identification of the C-terminus U-box, a domain related to RING-finger, in CHIP revealed it to have intrinsic E3 ubiquitin ligase activity. Later studies indicated that CHIP destabilized Hsp70/Hsp90 clients, glucocorticoid receptor (GR) and CFTR, effectively identifying CHIP as the first chaperone associated E3 ligase. Definitive evidence for a quality control role of CHIP was provided when it was shown to selectively ubiquitinate Hsp70/90-associated denatured luciferase but not its native form (McDonough and Patterson 2003).
CHIP, Fig. 1

Chaperone and cochaperone cycle. The events start with the presence of unfolded polypeptides which are recognized by HSP40 and delivered to ATP-bound “open” HSP70. Subsequent hydrolysis of ATP to ADP induces a “closed” conformation of HSP70 that has high affinity for the substrate. Nucleotide exchange factor (NEF) promotes the dissociation of ADP and binding of ATP with HSP70 which now has low affinity for substrate thus facilitating substrate release. HIP (Hsc70-interacting protein) opposes NEF. ATP-bound HSP70 is ready for another cycle. Multiple cochaperones influence the HSP reaction. CHIP targets HSP70-bound polypeptides for ubiquitination channeling them toward 26S proteasome-mediated degradation. Similarly, BAG-1 is a negative regulator of HSP70 “forward” cycle and uncouples nucleotide hydrolysis from substrate release. It has been shown to promote CHIP activity and facilitates DALIS (see Physiological function of CHIP - Immune system) formation. HOP (Hsp70-Hsp90 organizing protein) acts as a linker between HSP70 and HSP90 machinery. HOP binds “open” Hsp90 and acts as an attachment site for substrate-bound HSP70. P23 stabilizes “closed” HSP90. CHIP is known to target HSP90 bound clients for degradation but with lower affinity than HSP70 substrates

Structure of CHIP

The protein CHIP has two structural features – an N-terminus TPR domain (residues 26–131) and a C-terminus U-box domain (residues 232–298) separated by a central loosely structured coiled-coil region (residues 128–229). The entire TPR-domain consists of three pairs of TPR repeats and imparts the ability of protein-protein interaction to CHIP. Functional CHIP forms a dimer through its coiled-coil region. The C-terminus U-box domain imparts E3 ligase activity to CHIP; however like other U-box ligases, CHIP does not catalyze ubiquitin transfer to its substrates itself but simply acts as an adaptor which positions the substrate in precise proximity to the E2-ubiquitin thioester (E2-Ub).

An interesting structural feature of CHIP is that it forms an asymmetric homodimer, meaning that each protomer inherently adopts significantly different conformations in the dimer. The functional consequence of such an arrangement is that only one of the U-boxes in the CHIP dimer is active thus effectively displaying a “half-of-sites” activity which allows it to form monotonic polyubiquitin chains (Schulman and Chen 2005; Paul and Ghosh 2014).

Interaction with E2s

CHIP was previously shown to cooperate with the UbcH5 family of E2s, which is a stress-associated E2, to catalyze Lys-48-linked polyubiquitination. Later, CHIP was reported to interact with the dimeric ubiquitin E2 complex Ubc13-Uev1A, which catalyzes the synthesis of Lys-63-linked polyubiquitination. Analysis of crystal structures of mouse CHIP U-box in complex with Ubc13-Uev1a revealed a common Ser-Pro-Ala motif present in UbcH4, UbcH5, and Ubc13 that mediates, and is necessary for, their interaction with the CHIP U-box (Zhang et al. 2005; Xu et al. 2008). The physiological ramifications of the fact that CHIP can function with different E2s to catalyze distinct forms of polyubiquitination are yet to be studied in detail.

Regulation of CHIP

Below, we give a concise account of our current knowledge on the various regulatory mechanisms operating on the activity of CHIP under different physiological contexts (Paul and Ghosh 2014).

Transcriptional Regulation

The mRNA level of CHIP is upregulated under various stress conditions such as heat-shock, accumulation of mutant polyQ, and oxidative damage. CHIP gene expression is also controlled by TLR2 agonist peptidoglycan in RAW264.7 cells but not by LPS (TLR4 ligand) or CpG ODN (TLR9 ligand). Further, the expression of CHIP has been found altered in various human malignancies including breast, colorectal, and gastric cancer where its expression levels correlate highly with tumour prognosis.

Posttranscriptional Regulation

An instance of posttranscriptional regulation of CHIP mRNA has been reported in the context of bone morphogenesis. CHIP is downregulated in calvarial and osteoblast progenitor cells during osteoblast differentiation. In MC3T3-E1 cells, the microRNA miR-764-5p has been shown to inhibit the translation of CHIP mRNA by binding at its 3′-UTR which is essential for proper osteoblast differentiation.

Posttranslational Regulation

These modifications of CHIP likely dictate the recruitment of cofactors which in turn may participate in substrate selection and restrict the type and length of ubiquitin chains produced. CHIP is known to undergo regulatory ubiquitination in cells and in vitro which increases under conditions where the level and activity of CHIP are increased. Our knowledge of posttranslational modifications (PTMs) other than ubiquitination in regulating the activity of CHIP is still lacking. N- and C-terminal regions of CHIP have been proposed to contain functional phosphorylation sites, and CHIP has been shown to interact with multiple kinases (e.g., ERK5 and LIMK1) and phosphatases (e.g., Laforin) with potential downstream functional consequences for CHIP.

Half-Life

Regulation of half-life or stability of CHIP protein may be a possible mode of controlling its activity. For instance a study found that the TPR domain of CHIP when isolated were monomeric and stable, while its U-box domain formed dimers and had very low stability. However, more biochemical studies are needed to shed light on this important aspect of CHIP biology.

Protein Modulators

A number of proteins have been shown to interact with CHIP, either directly or indirectly, and regulate its activity. A brief description is outlined in Table 1.
CHIP, Table 1

Protein modulators of CHIP function

Name

Function

Effect on CHIP activity

S100A2 and S100P

Regulatory roles in a variety of cellular processes

Supresses E3 activity of CHIP by competing with substrate binding

Xap2

Dioxin receptor metabolism

Competes with CHIP for binding with Hsp90

OLA-1

Cytosolic ATPase, positively regulate the heat-shock response

Protects Hsp70 from CHIP-mediated degradation by competing with CHIP for binding at the C-terminal of Hsp70

HspBP1

Nucleotide release factor of Hsc70

Presumably induces conformational changes of the chaperone complex that keep ubiquitin acceptor sites of the substrate from the reach of CHIP

BAG1

Inhibits the chaperone activity of Hsp70/Hsc70 by promoting substrate release

Favors CHIP activity indirectly by facilitating Hsc70 cycle and Hsc70 recruitment to proteasome

BAG2

Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release

Inhibits the ubiquitin ligase activity of CHIP bound to Hsc70 by disrupting the interaction between CHIP and its E2, UbcH5b

BAG3

Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release

Indirectly stimulates the binding of CHIP to Hsp70 complex; cooperates with CHIP to promote CASA

BAG5

Favors forward cycle of Hsp70 by promoting nucleotide exchange

Inhibits E3 activity of CHIP, mechanism not known

HSJ1a

Cochaperone which facilitates forward cycle of Hsc70

Stimulates CHIP-mediated ubiquitination

S5a (Rpn10)

Maintains structural integrity of 26S proteasome; recongnizes ubiquitinated substrates

Favors degradative activity of CHIP by preventing formation of nondegradable forked ubiquitin chains catalyzed by CHIP-UbcH5

Ataxin-3

Deubiquitinase

Interacts with monoubiquitinated CHIP and regulates polyubiquitin chain length on its substrates

Subcellular Localization

Regulated nuclear localization of CHIP under different physiological contexts has been reported. Upon heat-shock of murine fibroblast cells, HSF1 and CHIP are known to rapidly translocate to the nucleus as a part of the response and reaccumulate in the cytoplasm during recovery stage. In rodent brain and primary cortical neurons, CHIP rapidly (within 5–10 minutes) and transiently (for upto 60 minutes) accumulated in the nucleus following heat-shock and oxygen-glucose deprivation which is linked to the ability of these cells to recover and survive. Although the identities of nuclear substrates of CHIP are obscure, although a few that have been reported till date include AR-97Q, p65, p53, RUNX1, and RUNX2.

CHIP also localizes to endoplasmic reticulum (ER). CHIP colocalizes with CFTR and Hsp70 at the ER membrane and is involved in CFTR biogenesis. Growth hormone receptor (GHR) is efficiently folded in the ER and under conditions of CHIP depletion both precursor and mature GHR accumulate inside the cells. Recently, a study linking ER stress and tauopathy i.e., neurodegenerative disease associated with the pathological aggregation of tau protein, reported that upon elicitation of ER stress (using glucose deprivation) the interaction between tau, a known target of CHIP, and CHIP significantly decreases leading to an accumulation of tau and consequent tauopathy.

Physiological Functions of CHIP

Maintenance of Protein Homeostasis

CHIP is well established as a quality control E3 ligase. Apart from homeostatic regulation under resting conditions, CHIP is known to regulate various stress activated signaling pathways (Hirsch et al. 2006; Edkins 2015; Paul and Ghosh 2015).

Quality Control in Endoplasmic Reticulum

Endoplasmic reticulum associated degradation (ERAD) pathway targets misfolded proteins for degradation in the ER. Recently, CHIP was shown to be required for proper biogenesis of two ERAD substrates, CFTR (Cystic fibrosis transmembrane receptor) and NCC (NaCl cotransporter).

Heat Stress

CHIP null mice are temperature sensitive and develop multiorgan apoptosis after heat-shock. CHIP is classically known to ubiquitinate denatured polypeptides bound to Hsp70. In addition, CHIP can also interact with nonnative and denatured proteins in an Hsp70-independent manner indicating an important role of CHIP during heat-stress.

Oxidative Stress

Our understanding of the well-known protective role of CHIP is challenged in oxidative stress. Overexpressed CHIP impaired survival of HT-22 cells upon glutamate exposure which induces oxidative stress in these cells. Interestingly, CHIP destablized endonuclease G and SENP3 under normal conditions in an Hsp70 dependent manner but not after H2O2 exposure.

Osmotic Stress

Exposure of mammalian cells to hyperosmolality activates a range of kinases such as p38MAPK, JNK, and ERKs which adjusts downstream gene expression to cope with the situation. Upon sorbitol treatment MEKK2 is dephosphorylated (by an unknown kinase) which leads to its CHIP mediated ubiquitination.

Protection from Stress-Induced Apoptosis

Under conditions of stress, cells upregulate CHIP to avoid stress-induced apoptotis. CHIP is reported to function through multiple modes. Apart from direct ubiquitination and clearance of aggregate-prone forms of proteins, CHIP induces the trimerization of HSF1 and facilitates a counter-stress transcriptional response. Further, CHIP degrades ASK1 (apoptosis signal-regulating kinase 1) and tAIF (truncated apoptosis-inducing factor) which in response to various stresses (such as oxidative stress, TNFα) activates JNK and triggers apoptosis thus providing a crucial component for cellular antiapoptotic machinery.

Aggresome Formation

Apart from degradation, cells can sequester denatured polypeptides into juxtanuclear detergent-insoluble ubiquitin-rich inclusion bodies called aggresomes. Cells lacking CHIP showed increased aggregates of iNOS and CFTRΔF508 and failed to form matured aggresomes. Polyubiquitination of both iNOS and CFTRΔF508 by CHIP were necessary for its transport via binding to HDAC6 and dynein (microtubule-based motor protein). Interestingly, CHIP itself colocalized with iNOS in the aggresome.

DNA Damage Repair

The protein XRCC1 acts as a scaffold for assembling DNA repair complexes on damaged DNA. BER (base excision repair) proteins which are in excess and are not involved in repair are ubiquitinated by CHIP, presumably in a chaperone-independent manner, and subsequently degraded by the 26S proteasome.

Aging and Senescence

Expression of CHIP decreases with age in mouse. Conversely, CHIP knock-out mice display accelerated aging. Comparable observations have been made in human cells. Mechanistically, the affinity of CHIP for certain proteins increases with aging, probably as a reflection of its cochaperone nature. The absence of CHIP is thought to facilitate deposition of these proteins which are susceptible to age-related structural instability (e.g., p53, tau, ERα, and ERβ).

Immune System

Antigen Processing/Presentation. The ubiquitin proteasome system (UPS) generates short 8–10 residue peptides that are loaded on MHC class I complexes and presented on the surface of antigen-presenting cells (APCs; dendritic cells and macrophages). RNAi-mediated knockdown of HSP90α or CHIP compromised their presentation on cell surface. Furthermore, ubiquitinated proteins can be stored in inclusion bodies called DALIS (dendritic cell aggresome-like induced structures) which allows DCs (dendritic cells) to coordinate maturation and antigen presentation. The chaperone and cochaperones CHIP, HspBP1, BAG-1, and BAG-3 are essential in regulating components for DALIS formation in mouse DCs and macrophages. CHIP and BAG-1 facilitates whereas HspBP1 opposes a proteasomal routing.

Proinflammatory Actions of CHIP

In macrophages and DCs, CHIP-mediated K63-linked polyubiquitination of Src and PKCζ induces their recruitment to the endosomal TLR4/9 complex, but not TLR3, and is essential for TLR-triggered activation of MAPK and NF-κB signaling and type I IFN production. In another report, CHIP-mediated ubiquitination of CARMA1 (caspase recruitment domain-containing membrane-associated guanylate kinase protein 1), a negative regulator of NF-κB signaling, through K27-linked polyubiquitin chains at K689 and K696 was found to be important for the activation of NF-κB. Interestingly, the knockdown of CHIP does not affect TNFα-induced NF-κB activation but significantly increases NF-κB activation and cytokine production upon CD3/CD28 cross-linking and PMA/Ionomycin (to activate PKC) stimulation. Another mechanism by which CHIP acts to inhibit inflammation-suppressive signals is by promoting Foxp3 degradation in an Hsp70-dependent manner. Foxp3 is a central regulator of the function and maintenance of T regulatory (Treg) cells. Moreover, overexpression of CHIP compromised Treg function and forced them to acquire a Th1 (T helper 1) type phenotype.

Anti-Inflammatory Actions of CHIP

In neonatal intestinal enterocytes, LPS-triggered TLR4-mediated NF-κB signaling induced Hsp70 expression which together with CHIP degrades TLR4 receptor establishing a negative feedback loop. Similarly, CHIP has been found to ubiquitinate and target IL-4Rα (interleukin-4 receptor α) for proteasomal degradation. IL-4Rα mediates actions of anti-inflammatory cytokines IL-4 and IL-13. In line, CHIP−/− mice develops spontaneous airway inflammation and activation of regulatory macrophages with increased serum IgE levels.

Behavior

In an interesting study, CHIP haplo-insufficient mice showed signs of poor limb coordination, cardiac hyperactivity, and anxiety. These same animals, on the other hand, were found normal with respect to body weight and temperature, breathing, memory, and tested somatosensory responses indicating a clear distinction of neurobehavioral aspects affected by CHIP.

Development

A role for CHIP in osteogenesis has been suggested. CHIP regulates cellular level of RUNX2 protein, a critical transcription factor required for osteoblast differentiation. During precursor cell commitment level of CHIP is kept low, presumably, to maintain high levels of functional RUNX2. During this phase, CHIP is one of the crucially underexpressed genes. An additional layer of suppression is provided by microRNA miR-764-5p which targets the 3′-UTR sequence of the CHIP mRNA to inhibit its translation.

CHIP in Diseases

Neurological Disorders

CHIP has been reported to regulate a number of proteins with relevance to neurodegenerative pathologies (Dickey et al. 2007; Kumar et al. 2012; Pratt et al. 2015; Paul and Ghosh 2015)

Parkinson’s Disease

The disease is caused by degeneration of neurons in the substantia nigra. At the molecular level, inactivating mutations of the E3 ligase Parkin causes its substrate Pael-R, a membrane receptor in the endoplasmic reticulum (ER), to accumulate causing ER stress-induced neuronal cell death. CHIP potentiates Parkin-mediated Pael-R ubiquitination. When bound to Hsp70 Pael-R is a weak substrate of Parkin and CHIP-mediated displacement of Parkin/Pael-R complex from Hsp70 is necessary for Parkin to attain its E3 activity toward Pael-R. CHIP itself has no E3 activity towards Pael-R.

Alzheimer’s Disease

Alzheimer’s disease is mainly caused by the deposition of cytotoxic neurofibrillary tangles caused by phosphorylated Tau protein. Tau is a tubulin-binding protein expressed in neurons and stabilizes microtubules. CHIP targets certain species, but not others, of phospho-Tau for proteasomal degradation in an Hsp70-dependent manner. Expression analysis of cDNA from a mice model of AD identified CHIP as a “hub” gene with significant reduction with aging.

Amyotropic Lateral Sclerosis (ALS)

Inherited forms of ALS is caused by aberrant deposition of the mutant Cu/Zn superoxide dismutase (SOD) 1, an enzyme that destroys free superoxide radicals, which presumably overloads the chaperone-proteasome system leading to neuronal deaths. CHIP promotes the degradation of mutant SOD1 indirectly by targeting SOD1-Hsp70 complexes to 26S proteasome.

Others

The importance of CHIP in some other neurological defects has also been reported which include Huntington’s disease, Lafora disease, Atherosclerosis, and Spino-cerebellar ataxia type-1.

Cardiac Diseases

Hypoxic conditions in cardiomyocytes, such as in myocardial infarction, activates HIF-1 signaling which suppresses CHIP expression and results in aberrant accumulation of p53, an established target of CHIP. Both overexpression of CHIP and Hsp90 inhibition by 17-AAG destabilize p53 and exert cardioprotective effects following infarction. Similarly, in a model of pulmonary hypertension, CHIP was shown to degrade Hsp70-bound GCH1 (GTP cyclohydrolase 1) which is the rate-limiting enzyme for generation of BH4, a rate limiting cofactor for the enzyme NO synthase (eNOS) in endothelial nitric oxide (NO) signaling.

Muscular Disorders

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease caused by expansion of a polyQ tract within the androgen receptor (AR) resulting in functional loss of motor neurons in the spinal cord and brainstem and manifested as progressive muscle weakness. Overexpression of CHIP has been correlated with cellular clearance of mutant AR and may have therapeutic potential. A protective advantage of CHIP downregulation has also been observed in a C. elegans model of Duchene muscular dystrophy, which is caused by loss-of-function mutation of the Dystrophin gene.

Cancers

The role of CHIP is differential across various cancer types. Although the inhibition of Hsp90 is always antitumorigenic, same is not true for CHIP. Below a brief description of the tumor-suppressive and oncogenic roles of CHIP are given (Sun et al. 2014).

CHIP as a Tumor Suppressor

In human breast, colorectal, and gastrointestinal cancers, CHIP levels are negatively correlated to tumor growth, metastasis, and survival. CHIP is identified as an important favorable prognostic marker in these scenarios. In line, CHIP inhibits anchorage-independent cell growth and migration of various breast cancer cells and is an important regulator of many critical oncogenic proteins including SRC-3, TRAF2, NF-κB, PTK6, and MIF. In various other cancers, CHIP has been reported to degrade a number of other oncoproteins such as pAkt, c-Myc, and HIF-1α.

CHIP as an Oncogene

In vascular smooth muscle cells, CHIP promotes degradation of proapoptotic FoxO1 in a phosphorylation dependent manner (Ser256 of FoxO1) and enhances proliferation in response to TNFα. In prostate cancer cell lines, PTEN was found to be a target of CHIP. In esophageal squamous cell carcinoma, the expression of CHIP was found to be significantly higher in metastatic lymph nodes as compared to primary tumors and low CHIP expression correlated with better survival and served as an independent prognostic marker.

Summary

CHIP has emerged as a critical regulator of a diverse array of biological processes including protein trafficking, stress-response, apoptosis, inflammation, morphogenesis, and several pathological conditions such as bone metabolism, neurological disorders, cardiac diseases, and cancers. In principle, CHIP mostly acts as a chaperone-dependent E3 ligase and channels its targets for proteasomal degradation. However, chaperone-independent degradative roles and nondegradative roles through catalysis of polyubiquitin chains of multiple linkages by CHIP have emerged and have significant cellular consequences (e.g., NF-κB signaling).

Thus, several questions remain to be answered before we approach toward a comprehensive understanding of CHIP biology:
  1. 1.

    Regulation of CHIP. Published literature indicates that CHIP is highly regulated at the transcriptional, posttranscriptional, and posttranslational levels including subcellular localization depending on the physiological requirements of the cell. What molecular players and mechanisms are responsible for the regulation of CHIP are not fully known.

     
  2. 2.

    Substrate selection/specificity. Are all chaperone clients, or in other words denatured proteins, are substrates of CHIP? Existing evidence suggests differently. CHIP has both chaperone-dependent and -independent substrates. Gross structural deformation of substrates undoubtedly plays an integral role in triggering association with CHIP. However, specific posttranslational modifications (e.g., phosphorylation) can also trigger or preclude association, indicating a level of specificity of target selection by CHIP. Also, having a more broad knowledge of the various CHIP-interacting proteins, under different physiological contexts, is expected to yield important insights.

     
  3. 3.

    E2 selection. As CHIP can promote ubiquitin chains of multiple linkages, it will be necessary to understand how CHIP selects its E2 (or vice versa) under a particular condition?

     

Notes

Acknowledgments

Financially supported by grants from CSIR, India (EMPOWER-OLP-002, MEDCHEM-BSC0108 & CSIR-MAYO: MLP-0017) and DST Nano Mission programme (SR/NM/NS-1058/2015) to Dr. Mrinal K Ghosh.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Proteomics Program, Novo Nordisk Foundation Center for Protein ResearchUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of MicrobiologyBarrackpore Rastraguru Surendranath CollegeBarrackpore, KolkataIndia
  3. 3.Cancer Biology and Inflammatory Disorder DivisionCouncil of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB)KolkataIndia