Endoplasmic Reticulum Associated Protein Degradation (ERAD) in the Pathology of Diseases Related to TGFβ Signaling Pathway: Future Therapeutic Perspectives

Nesrin Gariballa, Bassam R. Ali

Research output: Contribution to journalReview articlepeer-review

10 Citations (Scopus)

Abstract

The transforming growth factor signaling pathway (TGFβ) controls a wide range of cellular activities in adulthood as well as during embryogenesis including cell growth, differentiation, apoptosis, immunological responses and other cellular functions. Therefore, germline mutations in components of the pathway have given rise to a heterogeneous spectrum of hereditary diseases with variable phenotypes associated with malformations in the cardiovascular, muscular and skeletal systems. Our extensive literature and database searches revealed 47 monogenic diseases associated with germline mutations in 24 out of 41 gene variant encoding for TGFβ components. Most of the TGFβ components are membrane or secretory proteins and they are therefore expected to pass through the endoplasmic reticulum (ER), where fidelity of proteins folding is stringently monitored via the ER quality control machineries. Elucidation of the molecular mechanisms of mutant proteins’ folding and trafficking showed the implication of ER associated protein degradation (ERAD) in the pathogenesis of some of the diseases. For example, hereditary hemorrhagic telangiectasia types 1 and 2 (HHT1 and HHT2) and familial pulmonary arterial hypertension (FPAH) associated with mutations in Endoglin, ALK1 and BMPR2 components of the signaling pathway, respectively, have all exhibited loss of function phenotype as a result of ER retention of some of their disease-causing variants. In some cases, this has led to premature protein degradation through the proteasomal pathway. We anticipate that ERAD will be involved in the mechanisms of other TGFβ signaling components and therefore warrants further research. In this review, we highlight advances in ER quality control mechanisms and their modulation as a potential therapeutic target in general with particular focus on prospect of their implementation in the treatment of monogenic diseases associated with TGFβ components including HHT1, HHT2, and PAH. In particular, we emphasis the need to establish disease mechanisms and to implement such novel approaches in modulating the molecular pathway of mutant TGFβ components in the quest for restoring protein folding and trafficking as a therapeutic approach.

Original languageEnglish
Article number575608
JournalFrontiers in Molecular Biosciences
Volume7
DOIs
Publication statusPublished - Oct 29 2020

Keywords

  • ALK1
  • BMPR2
  • ERAD
  • endoglin
  • hereditary hemorrhagic telangiectasia
  • pulmonary arterial hypertension
  • transforming growth factor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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