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UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator.

ABSTRACT: Members of the ubiquitin-like protein family are known for their ability to modify substrates by covalent conjugation. The highly conserved ubiquitin relative UBL5/Hub1, however, is atypical because it lacks a carboxy-terminal di-glycine motif required for conjugation, and the whole E1-E2-E3 enzyme cascade is likely absent. Though the conjugation-mediated role of UBL5/Hub1 is controversial, it undoubtedly functions by interacting non-covalently with its partners. Several interactors of UBL5/Hub1 identified to date have suggested broad stress-responsive functions of the protein, for example, stress-induced control of pre-mRNA splicing, Fanconi anemia pathway of DNA damage repair, and mitochondrial unfolded protein response. While having an atypical mode of function, UBL5/Hub1 is still a stress protein that regulates feedback to various stimuli in a similar manner to other ubiquitin-like proteins. In this review, I discuss recent progress in understanding the functions of UBL5/Hub1 and the fundamental questions which remain to be answered.

SUBMITTER: Chanarat S

PROVIDER: S-EPMC8431670 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The beliefs that antipsychotic drugs (APDs) are 1) effective only to treat delusions and hallucinations (positive symptoms), 2) that typical and atypical APDs differ only in ability to cause extrapyramidal side effects, and 3) that their efficacy as antipsychotics is due solely to their dopamine D2 receptor blockade are outmoded concepts that prevent clinicians from achieving optimal clinical results when prescribing an APD. Atypical APDs are often more effective than typical APDs in treating negative symptoms, cognitive impairment, and mood symptoms as well as reducing the risk for suicide and decreasing aggression. This applies not only to those diagnosed with schizophrenia or schizoaffective disorder but also to bipolar disorder, major depression, and other psychiatric diagnoses. The greater advantage of an atypical APD is not evident in all patients for every atypical APD due, in part, to individual differences in genetic and epigenetic endowment and differences in the pharmacology of the atypical APDs, their mode of action being far more complex than that of the typical APDs. A common misconception is that among the atypical APDs, only clozapine is effective for reducing psychosis in treatment-resistant schizophrenia. Aripiprazole, lurasidone, olanzapine, and risperidone also can be more effective than typical APDs for treatment-resistant schizophrenia; clozapine is uniquely indicated for reducing the risk for suicide. The ability of the atypical APDs to improve cognition and negative symptoms in some patients together with lower propensity to cause tardive dyskinesia (an underappreciated advantage) leads to better overall outcomes. These advantages of the atypical APDs in efficacy and safety are due, in part, to initiation of synaptic plasticity via direct and indirect effects of the atypical APDs on a variety of proteins, especially G proteins, and release of neurotrophins (e.g., brain-derived neurotrophic factor). The typical APDs beneficial effects on psychosis are mainly the result of D2 receptor blockade, which can be associated with serious side effects and lack of tolerability.

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UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator.

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