ER-Associated Degradation in Health and Disease – from Substrate to Organism Asmita Bhattacharya1,2 and Ling Qi1,3,*
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© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs232850. doi:10.1242/jcs.232850 REVIEW SUBJECT COLLECTION: CELL BIOLOGY AND DISEASE ER-associated degradation in health and disease – from substrate to organism Asmita Bhattacharya1,2 and Ling Qi1,3,* ABSTRACT note Sel1L is also known as Hrd3, and Hrd1 as SYVN1) – the focus – The recent literature has revolutionized our view on the vital of this Review is central to the most-conserved and best- importance of endoplasmic reticulum (ER)-associated degradation characterized branch of mammalian ERAD (Mueller et al., 2008, (ERAD) in health and disease. Suppressor/enhancer of Lin-12-like 2006; Ye et al., 2004). The ERAD process begins with the selection (Sel1L)–HMG-coA reductase degradation protein 1 (Hrd1)-mediated of the substrate protein; this is based on either glycosylation tags, ERAD has emerged as a crucial determinant of normal physiology mannose trimming status and/or conformational change, and is and as a sentinel against disease pathogenesis in the body, in a aided by chaperones, such as 78-kDa glucose-regulated protein α largely substrate- and cell type-specific manner. In this Review, we (Grp78; also known as HSPA5), ER degradation-enhancing - highlight three features of ERAD, constitutive versus inducible ERAD, mannosidase-like protein (Edem) family proteins and osteosarcoma quality versus quantity control of ERAD and ERAD-mediated amplified 9 (Os9) (Araki and Nagata, 2011; Bernasconi et al., 2010; regulation of nuclear gene transcription, through which ERAD Christianson et al., 2008; Hegde and Ploegh, 2010; Olzmann et al., exerts a profound impact on a number of physiological processes. 2013; Smith et al., 2011; van der Goot et al., 2018). In a second step, the substrate is retro-translocated into the cytosol through the KEY WORDS: Sel1L-Hrd1 ERAD, Health, Disease, Constitutive polytopic dislocon Hrd1; Hrd1 itself forms a ubiquitin-gated ERAD, Inducible ERAD, ERAD substrate, Quality control, Quantity channel activated by auto-ubiquitylation (Baldridge and Rapoport, control, Nuclear gene transcription 2016; Carvalho et al., 2010; Christianson et al., 2012). Other potential dislocon proteins, such as degradation in endoplasmic Introduction reticulum protein (Derlin) family members – Derlin-1, Derlin-2 or Secreted proteins, such as hormones and growth factors, as well as Derlin-3 – have been identified as possibly working together with transmembrane receptors, critically regulate nearly all aspects of Hrd1, but their role needs further characterization in mammalian life, including food intake, water balance, growth, metabolism and systems (Lilley and Ploegh, 2004; Ye et al., 2004). The adaptor immunity. The endoplasmic reticulum (ER) is a specialized cellular protein Sel1L is indispensable for the stability and function of Hrd1 compartment where the folding and maturation of most of these (Mueller et al., 2008, 2006; Sun et al., 2014; Vashistha et al., 2016). proteins take place (Hegde and Lingappa, 1997). Aberrations in Subsequent to the retro-translocation, substrates are ubiquitylated these complex thermodynamic folding processes and kinetic by Hrd1 (Kikkert et al., 2004) and targeted for proteasomal parameters can disrupt cellular homeostasis and lead to degradation by the ATPase valosin-containing protein Vcp (also debilitating diseases, such as liver and lung diseases, and diabetes known as p97) and other ubiquitin-modifying enzymes (Ernst et al., (Braakman and Bulleid, 2011; Wiseman et al., 2007). ER- 2009; Meyer et al., 2012) (Fig. 1A). In addition, other E3 ligases, associated degradation (ERAD) is a highly conserved, major such as glycoprotein 78 (Gp78, also known as AMFR), membrane- regulatory system that guards against such events, thereby associated ring-CH-type finger 6 (March6), ring finger protein 5 maintaining proteostasis within the ER (Aridor and Balch, 1999; (Rnf5, also known as Rma1) and tripartite motif containing 13 Guerriero and Brodsky, 2012). Despite being well-characterized at (Trim13), may work either in parallel or together with Hrd1; the biochemical level, which has been reviewed extensively however, these systems remain poorly characterized (Altier et al., elsewhere (Christianson and Ye, 2014; Merulla et al., 2013; 2011; Fang et al., 2001; Hassink et al., 2005; Younger et al., 2006; Olzmann et al., 2013), the significance of ERAD on a systemic Zhang et al., 2015) and will not be discussed here. Biochemical (patho)physiological scale has, until recently, remained unknown studies have identified some proteins as possible ERAD substrates (Hwang and Qi, 2018; Qi et al., 2017). This Review discusses the in mammalian cell lines, such as mutant α-antitrypsin, mutant emerging roles of ERAD in health and disease, without which, our transthyretin, cystic fibrosis transmembrane conductance regulator understanding of pathogenesis of a large number of diseases (CFTR) and unassembled Cd147 (also known as BSG) remains incomplete. (Christianson et al., 2012; Christianson et al., 2008; Liu et al., The suppressor/enhancer of lin-12-like (Sel1L)–HMG-coA 1997; Sifers et al., 1988; Tyler et al., 2012; Ward et al., 1995); reductase degradation protein 1 (Hrd1) protein complex (Fig. 1A; however, whether or not these proteins are bona fide endogenous ERAD substrates remains to be verified in vivo. Deletion of any key component of ERAD, such as Sel1L, Hrd1, 1Department of Molecular & Integrative Physiology, University of Michigan Medical Derlin or Vcp, results in embryonic lethality in mice (Dougan et al., School, Ann Arbor, MI 48105, USA. 2Graduate Program of Genetics, Genomics and 2011; Eura et al., 2012; Francisco et al., 2010; Müller et al., 2007), Development, Cornell University, Ithaca, NY 14853, USA. 3Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan underscoring the physiological significance of ERAD in Medical School, Ann Arbor, MI 48105, USA. development. Recently, cell type-specific knockout mice of specific ERAD genes have been reported, revealing that ERAD is *Author for correspondence ([email protected]) linked to a plethora of physiological conditions, often in a substrate- A.B., 0000-0002-5669-8036; L.Q., 0000-0001-8229-0184 specific manner (Qi et al., 2017). These findings have allowed us to Journal of Cell Science 1 REVIEW Journal of Cell Science (2019) 132, jcs232850. doi:10.1242/jcs.232850 A B Fig. 1. Overview over physiological ERAD and emerging paradigms. (A) Sel1L–Hrd1- ER ER mediated ERAD. ERAD is a highly conserved cellular system that is responsible for the Chaperones Substrates Chemical agents retrotranslocation of substrate proteins from the Substrates proAvp Pre-BCR Tm Tg ER to the cytosol for proteasomal degradation. This process starts with substrate recruitment by chaperones (Grp78, Os9, Xtp3b, Edem1– UPR Edem3) and adaptor proteins (Sel1L, Derlin Pomc Sel1L proteins), followed by their retrotranslocation through the dislocon channel (Hrd1 or Derlin), and ubiquitylation by an E3 ligase (Hrd1) and ERAD ATPase (Vcp), before degradation at the proteasome. (B–D) Recent in vivo studies have Derlin highlighted three major conceptual advances in Crebh mammalian ERAD biology. (B) Constitutive versus inducible ERAD. ERAD may function in Hrd1 a constitutive capacity to maintain optimal Vcp Food B cell Nucleus levels of key proteins regulating critical maturation intake physiological process such as food intake, Proteasome water and energy balance, and B cell development, or in an inducible capacity, Fgf21 whereby ERAD gene expression is triggered by drug-induced UPR. (C) Quality versus quantity Water Systemic balance energy control by ERAD. Physiological ERAD has balance been reported to perform both quality control of misfolded substrates, thus ensuring fidelity of Constitutive Inducible production and protecting against their Cytosol Cytosol aggregation and loss-of-function effects, and quantity control of folding-competent C D substrates, thereby regulating their abundance and guarding against over-activation and gain- Cytosol α ER Ire1 of-function effects. (D) ERAD-regulated transcription. ERAD influences gene expression in the nucleus through the direct ERAD manipulation of ER-related transcription ERAD α– X factors; for example, the Ire1 Xbp1s axis of P0 XBP1u UPR, and the Crebh–Fgf21 axis in metabolism and growth. Direct degradation of nuclear proAvp Crebh transcription factors by ERAD is not shown proINS Xbp1s here. Tg, thapsigargin; Tm, tunicamycin; Pomc proINS, proinsulin; uXBP1, unspliced XBP1; S1P and S2P, Golgi site-specific proteases. S1P, S2P Quality control ER Quantity control ERAD, ER Golgi chaperones, Pre-BCR Xbp1s lipid Dgat2 metabolism Mogat2 Ire1α Gpat3 Fas Crebh-N Fgf21, Apcs, ERAD Apoa4, Cidec Crebh Cytosol Cytosol Nucleus map out the stipulations that are necessary for the identification of a fidelity and abundance of ER protein production, and communicate bona fide ERAD substrate in vivo (Box 1), and significantly external cues to gene expression in the nucleus. changed our view of the physiological and pathological importance of ERAD. In this Review, we highlight the hallmark features Constitutive versus inducible ERAD obtained from these recent animal studies: constitutive versus Accumulation of misfolded proteins triggers the ‘unfolded protein inducible ERAD, quality versus quantity control by ERAD, and response’ (UPR), which acts to reduce ER load and increase the ERAD-mediated regulation of gene transcription