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

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.

Keywords: ALK1; BMPR2; ERAD; endoglin; hereditary hemorrhagic telangiectasia; pulmonary arterial hypertension; transforming growth factor.

FIGURE 1

The TGF beta SMAD-dependent signaling pathway. The diagram shows some of the major components of the TGFβ signaling pathway. SMAD-dependents signal transduction is initiated with the binding of the ligands (e.g., TGFβ, BMP, activins etc.) to the serine/threonine type II receptor that phosphorylates and activates the type I receptor which causes dimerization of the type II and type I receptors in a heterotetrameric complex. The signal is then propagated to the nucleus through phosphorylation of SMAD transcription factors. The image represents only few of the ligands/receptors/SMADs possible signal transduction combinations.

FIGURE 2

ERAD mechanism for misfolded glycoprotein through the HRD-1/SEL-1L complex. Triglycosylated form of protein-bound oligosaccharide (Gl₃Man₉GlcNac₂) is processed by glucosidase enzymes (GluI/II) that cleaves off two glucose molecules. This is followed by cycles of interaction between the nascent protein and lectins such as Calnexin and Calreticulin (CNX/CRT), that binds specifically to monoglucosylated oligosaccharides (GlMan₉GlcNac₂) and ensure the proper folding of newly synthesized protein. This cycling effect is generated by the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT), that transfers back a glucose residue to the improperly folded protein to enable further encounters with the ER chaperones (CNX/CRT). A properly folded protein is then released after the cleavage of the remaining glucose molecule. Properly formed protein is dispatched to its functional destination, while misfolded protein that cannot reach its mature form will undergo mannose cleavage by ER α1,2-mannosidase I (ERMan1), which produces Man8GlcNAc2. Terminal mannose cleavage (α mannose) function as a recognition signal for ERAD lectins OS-9 and XTP3-B that recognize and binds to exposed mannose residues after cleavage of α mannose. The three chaperones EDEM1, OS9 and XTP3-B function together as recognition complex that interacts with misfolded proteins and the HRD-1/SEL-1L retrotranslocation channel. Derlins which are candidates for the translocon channel also interacts with the EDEMs and facilitates the interaction of EDEMs with cytosolic AAA-ATPase p97, that provides ATP hydrolysis for successful extraction of mutant proteins. Retrotranslocation is coupled by Uniquitination, a process that targets proteins for degradation by 26S proteasome by tagging them with ubiquitin chains.