The E3 ubiquitin ligase CHIP in normal cell function and in disease conditions

Abstract

In eukaryotic cells, ubiquitination and proteasomal degradation is an essential mechanism for regulating protein functions. For example, critical signaling proteins play their roles by controlling different cellular functions. Once a signaling protein has been activated, its activity needs to be quickly downregulated by different mechanisms, including ubiquitination/proteasome regulation. Failure to regulate the activity or expression levels of these proteins may cause human diseases. Protein ubiquitination involves a cascade of biochemical processes and requires three types of ubiquitin enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase. Among these enzymes, E3 ubiquitin ligases play a specific role in recognizing specific protein substrates. There are several structurally diverse groups of E3 ubiquitin ligases in eukaryotic cells, and one type of these E3 ligases is the U‐box ubiquitin ligases. Carboxyl terminus of HSP70‐interacting protein (CHIP) is a member of a family of U‐box E3 ligases. It plays critical roles in multiple organs and tissues in the body. In this review article, we provide an update on some of the most recent discoveries about CHIP in normal physiological function and in disease.

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

“…One prime example of such ligases is CHIP encoded by the STUB1 gene and whose genomic alterations cause spinocerebellar ataxia ( Shi et al, 2013 ). Thanks to its ability to bind to cellular chaperones such as HSP70 and HSP90, CHIP mediates the ubiquitination of misfolded proteins, thereby targeting them for subsequent degradation by 26S proteasomes ( Edkins, 2015 ; Wang et al, 2020 ). Such misfolded proteins typically encompass defective ribosomal products (DRIPS) which are generated during protein biosynthesis as a consequence of ribosomal mistranslation ( Yewdell et al, 1996 ).…”

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

“…In cancer the pathogenic mechanisms of CHIP are less clear (216). Several studies on breast cancer cells have indicated CHIP as tumor suppressor (212,(217)(218)(219).…”

Ubiquitin Ligases Involved in the Regulation of Wnt, TGF-β, and Notch Signaling Pathways and Their Roles in Mouse Development and Homeostasis

“…A typical example of U-box-type ubiquitin ligase is the C terminus of the Hsc70-interacting protein (CHIP) [26]. Upon heat stress, CHIP recognizes its substrates in the context of activated heat shock proteins, controlling the stability and fate of misfolded proteins.…”