Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2023-08, Vol.24 (8), p.312-333
• Main Authors: Badawi, Sally, Mohamed, Feda E., Varghese, Divya Saro, Ali, Bassam R.
• Format: Article
• Language: English
• Subjects: animal model; Animal models; Animals; cellular disease model; cellular knockout; Degradation; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation; endoplasmic reticulum‐associated protein degradation (ERAD); ERAD genetic diseases; Genetic diversity; Homeostasis; Humans; Mammals - genetics; Mammals - metabolism; Phenotype; Phenotypes; Protein folding; Proteins - metabolism; Proteolysis; Quality control
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12902

Endoplasmic reticulum‐associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD‐related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single‐gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway. Degradation of unassembled, misfolded, and other defective proteins is mediated by a major quality control mechanism, named the endoplasmic reticulum‐associated protein degradation (ERAD). Throughout this manuscript, we present the various genetically manipulated higher cellular and mammalian animal models that were depleted for specific ERAD components. Additionally, we present the various single‐human disorders encoded by ERAD components genes and involved in ERAD's various stages.