Ubiquitin C-terminal hydrolase L1 interacts with choline transporter in cholinergic cells

Hartnett, Sigurd; Zhang, Fan; Abitz, Allison; Li, Yifan

doi:10.1016/j.neulet.2014.02.007

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…UCHL1 siRNA gene knockdown was performed as described previously[17] with some modifications. Briefly, C2C12 cells were grown in GM to desired confluence.…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation

Gao

Hartnett

2017

Biochemical and Biophysical Research Communications

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Skeletal muscles are dynamic tissues that possess regenerative abilities, which require multiple processes and regulatory factors. Ubiquitin C-Terminal Hydrolase L1 (UCHL1), which is primarily expressed in neuronal tissues, was upregulated in skeletal muscles in disease conditions but its functional role in skeletal muscles is unknown. Using mouse myoblast cells C2C12 as an in vitro model, this study reported that UCHL1 elicits different regulation in myoblast cell proliferation and differentiation. We first observed that UCHL1 protein level was continuously declined during cell differentiation. Gene knockdown of UCHL1 by siRNA resulted in a significant decrease in cell proliferation but marked acceleration of cell differentiation and myotube formation. Meanwhile, UCHL1 gene knockdown upregulated myogenic factors myoD and Myogenin (MyoG). In mice, UCHL1 was significantly upregulated in denervated skeletal muscle. Overall, these novel data suggest that UCHL1 may play a role in myogenesis by promoting myoblast proliferation and inhibiting differentiation.

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“…UCHL1 siRNA gene knockdown was performed as described previously[17] with some modifications. Briefly, C2C12 cells were grown in GM to desired confluence.…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation

Gao

Hartnett

2017

Biochemical and Biophysical Research Communications

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“…Ubiquitination proteolytically cleaves synaptic proteins or interferes with trafficking of such proteins, including the CHT (Buttner et al, 2001;Hartnett et al, 2014;Meyer et al, 1986;Yamada et al, 2012).…”

Section: Elevated Levels Of Poly-ubiquitylated Cht In Stsmentioning

confidence: 99%

“…Ubiquitination can occur in diverse ways, including conjugation to just one residue in its substrate (mono-ubiquitination) or multiple times to this residue, with the initial ubiquitin serving as the target for additional ubiquitination (poly-ubiquitination). Beyond the classical ubiquitin-dependent proteolysis, ubiquitination may interfere with numerous other aspects of the regulation and functions of proteins, such as the intracellular transport of proteins (e.g., Buttner et al, 2001; Schmidt et al, 2021; Lopez-Castejon, 2019; Kwon and Ciechanover, 2017), including of CHTs in vitro (Hartnett et al, 2014; Cuddy et al, 2012; Foot et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

Carmon

Haley

Parikh

et al. 2022

Preprint

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Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue solely by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here we investigated a post-translational modification of CHTs – poly-ubiquitination - and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in two brain regions, but not spleen, were higher in STs than in GTs. Activation of the innate immune system by systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) elevated ubiquitinated CHT levels in cortex and striatum of GTs only, suggesting ceiling effects in STs. In spleen, LPS increased levels of most cytokines in both phenotypes. In cortex, LPS particularly robustly increased levels of the chemokines CCL2 and CXCL10. Phenotype-specific increases were restricted to GTs, again suggesting ceiling effects in STs. These results indicate that interactions between elevated brain immune modulator signaling and CHT regulation are essential components of the neuronal underpinnings of the addiction vulnerability trait indexed by sign-tracking.Significance StatementSign-tracking rats (STs) have merged as a fruitful animal model for determining the neuro-behavioral foundations, including the cholinergic-attentional control deficits, which heighten the risk for the manifestation of addictive behaviors. The results from the present experiments suggest that, in STs, elevated levels of neuro-immune signaling may interact with a post-translational modification of choline transporters that yields a relatively low transporter capacity. Furthermore, the effects of activation of the innate immune system, by administrating the endotoxin lipopolysaccharide, mechanistically supported such an interaction. The results extend research on the neuronal vulnerabilities for addictive behaviors to the role of neuro-immune signaling and suggests a new role of neuro-immune modulators in influencing complex cognitive-motivational traits.

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“…Ub-mediated degradation of essential enzymes may have particular importance in the central nervous system. Using TUBEs, it was shown that Ub carboxy-terminal hydrolase 1 (UCHL1) antagonizes ubiquitylation of choline transporter (CHT) in a cholinergic neuron model [76]. While K48-linked polyubiquitylation is typically considered to target proteins for degradation, TUBEs identified noncanonical Ub-dependent degradation mechanisms, as K63linked HIF1A ubiquitylation signaling degradation by the ALS, expanding the known roles of Ub in intracellular proteolysis [77].…”

Section: Study Of the Ubiquitylation Of Specific Proteinsmentioning

confidence: 99%

Using Ubiquitin Binders to Decipher the Ubiquitin Code

Mattern

Sutherland

Kadimisetty

et al. 2019

Trends in Biochemical Sciences

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Post-translational modifications (PTMs) by ubiquitin (Ub) are versatile, highly dynamic, and involved in nearly all aspects of eukaryote biological function. The reversibility and heterogeneity of Ub chains attached to protein substrates have complicated their isolation, quantification, and characterization. Strategies have emerged to isolate endogenous ubiquitylated targets, including technologies based on the use of Ub-binding peptides, such as TUBEs (Tandem-repeated Ubiquitin-Binding Entities). TUBEs allow the identification and characterization of ubiquitin chains, novel substrates for deubiquitylases (DUBs) and Ub ligases (E3s). Here we review their impact on purification, analysis of pan or chain-selective polyubiquitylated proteins and underline the biological relevance of this information. Together with peptide aptamers and other Ub affinity-based approaches, TUBEs will contribute to unravelling the secrets of the Ub-code. The Complexity of the Ubiquitin CodeUbiquitination of proteins is a significant regulatory process that affects almost all cellular functions. Ubiquitin (Ub) is a small, compact, and highly conserved 76 amino acid protein. The C-terminus of Ub is attached by an isopeptide bond to the Ɛ-amino group of lysine residues on target proteins. After Ub is attached to a protein, this proximal Ub can act as a substrate for additional Ubs, which are conjugated to any of its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) or to its N-terminal methionine (M1) [1]. Protein ubiquitylation was first described as a signal for proteasomal degradation. The so called Ub-proteasome system (UPS) (see Glossary) uses mainly K48 and K11 polyubiquitylation as signals for substrate recognition [2,3]. The 26S proteasome include subunits that contain Ub-binding domains (UBDs) (Box 1) that participate in the binding of ubiquitin chains [4,5]. The binding and disassembly of many different types of Ub chains vary in both length and linkage specificity [6,7]. Although the presence of one Ub chain type is not by itself indicative of one function, accumulated evidence supports the existence of certain generic roles. For instance, proteasome inhibition leads to accumulation of ubiquitylated proteins containing all seven different types of Ub linkages except for K63 [8], strongly suggesting that K63 chains do not primarily target proteins to proteasomes. K63 Ub chains drive proteolysis primarily by the autophagylysosome system (ALS) [2] and might mediate DNA repair and other signaling pathways. Not much is known about the functions and mechanisms of more atypical linkages such Lys6, Lys27, Lys29, Lys33, and Met1 [9]. This Ub chain complexity known as the "Ub-code" includes mono-and multi-mono-Ub modifications, chains mixing multiple Ub linkages and other Ub-Like molecules (UbL). The biological relevance of most of these complex chains remains to be elucidated [10,11].

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Ubiquitin C-terminal hydrolase L1 interacts with choline transporter in cholinergic cells

Cited by 11 publications

References 31 publications

Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation

Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

Using Ubiquitin Binders to Decipher the Ubiquitin Code

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