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Regulation of Antimicrobial Pathways by Endogenous Heat Shock Proteins in Gastrointestinal Disorders

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Regulation of Antimicrobial Pathways by Endogenous Heat Shock Proteins in Gastrointestinal Disorders Review Regulation of Antimicrobial Pathways by Endogenous Heat Shock Proteins in Gastrointestinal Disorders Emma Finlayson-Trick 1 , Jessica Connors 2, Andrew Stadnyk 1,2 and Johan Van Limbergen 1,2,* 1 Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Room 7-C, Halifax, NS B3H 4R2, Canada; emma.fi[email protected] (E.F.-T.); [email protected] (A.S.) 2 Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Dalhousie University, IWK Health Centre, 5850/5980 University Avenue, Halifax, NS B3K 6R8, Canada; [email protected] * Correspondence: [email protected]; Tel.: +902-470-8746; Fax: +902-470-7249 Received: 31 August 2018; Accepted: 26 September 2018; Published: 28 September 2018 Abstract: Heat shock proteins (HSPs) are essential mediators of cellular homeostasis by maintaining protein functionality and stability, and activating appropriate immune cells. HSP activity is influenced by a variety of factors including diet, microbial stimuli, environment and host immunity. The overexpression and down-regulation of HSPs is associated with various disease phenotypes, including the inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). While the precise etiology of CD remains unclear, many of the putative triggers also influence HSP activity. The development of different CD phenotypes therefore may be a result of the disease-modifying behavior of the environmentally-regulated HSPs. Understanding the role of bacterial and endogenous HSPs in host homeostasis and disease will help elucidate the complex interplay of factors. Furthermore, discerning the function of HSPs in CD may lead to therapeutic developments that better reflect and respond to the gut environment. Keywords: heat shock protein; Crohn’s disease; inflammatory bowel disease; NOD2; immune homeostasis 1. Introduction Crohn’s disease (CD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract and a major form of inflammatory bowel disease (IBD). The prevalence of CD differs worldwide, with Europe and Canada having among the highest rates at 322 and 319 per 100,000 persons, respectively [1,2]. While the precise cause of CD is unclear, it is widely accepted that disease arises from a complex interaction between genetic and environmental factors that disrupt normal host-microbe interactions in the gut. The breakdown of intestinal mucosal barrier function is a key feature of CD pathogenesis. Intestinal epithelial cells play an active role in maintaining immune homeostasis by forming a barrier between the underlying tissues and the microbe-rich luminal environment [3]. The contribution of genetics in the pathophysiology of CD is demonstrated by numerous CD-risk associated polymorphisms in genes relevant to epithelial integrity and innate immune recognition [4]. There is also an expanding group of genes involved in monogenic IBD that are associated with significant intestinal epithelial barrier dysfunction [5]. However, the ≥200 susceptibility loci identified to date account for only 26% of CD variance [6]. This “missing heritability” in turn is determined by an estimation of genetic risk based on twin concordance studies, variants associated with gene expression Gastrointest. Disord. 2019, 1, 39–56; doi:10.3390/gidisord1010005 www.mdpi.com/journal/gastrointestdisord Gastrointest. Disord. 2019, 1 40 regulation rather than protein-altering variants, and a gene–environment/microbiome interaction that has proven difficult to model without a better understanding of environmental triggers [7–10]. Intestinal epithelial cells that are subjected to stress have the intrinsic ability to resist injury via various cytoprotective responses. Of these, endogenous heat shock proteins (HSPs) represent a major mechanism for protecting intestinal epithelial cell function and viability against a variety of environmental and physiological stressors. HSPs are found in all organisms from bacteria to humans and are among the most highly conserved proteins currently known [11]. HSPs are constitutively expressed at low levels but can be potently upregulated in response to a range of cellular stresses including nutrient depravation, oxidative stress, inflammation, and infections [12]. As molecular chaperones, HSPs assist in the folding of newly synthesized polypeptides and assembly of multiprotein complexes, prevent abnormal protein folding or aggregation, maintain protein conformation to facilitate binding, mediate the intracellular protein trafficking, and degrade damaged proteins via the ubiquitin-proteasome pathway [13–15]. In addition to intracellular functions, HSPs can be released extracellularly where they activate immune cells by processing and loading peptide onto either class I or II MHC molecules through direct or cross-presentation [16]. In recent years, studies in CD patients have demonstrated interesting relationships between HSPs (both self and bacterial) and inflammation. CD patients with active disease display significantly increased intestinal HSP expression [17,18]. Therapies that cause overexpression, or alternatively down-regulation, of specific HSPs have been considered as potential supplemental therapies for CD treatment [19–23]. Nonetheless, self and bacterial HSPs could represent an important environmentally-regulated and disease-modifying factor in the development of different CD phenotypes. Here, we review the current understanding of HSPs in mediating host inflammatory responses in CD, and we describe ongoing studies of bacterial HSPs in CD pathogenesis and protection. 2. HSP Families HSPs are categorized into six families based on their molecular weight: small HSPs (sHSPs), HSP40, HSP60, HSP70, HSP90, and large HSPs (lHSPs) (Figure1). 2.1. Small HSPs sHSPs are structurally defined by a conserved β-sandwich α-crystallin domain flanked by non-conserved N- and C-terminal sequences [24]. While most prokaryotes contain only one or two sHSP genes, some pathogenic bacteria contain none and some symbiotic bacteria contain ≥10 sHSP genes [25]. In comparison to prokaryotes, sHSPs reportedly evolved independently in the main eukaryotic lineages, including animals, plants and fungi [26]. There are eleven ubiquitous sHSPs encoded by HSPB genes that range in size from 12–42 kDa, with the most prominent members being HSP10 and HSP27 that function in the mitochondria and cytosol/nucleus, respectively. Most sHSPs cooperate and co-assemble into large ensembles and, unlike large HSPs, function in an ATP-independent manner [27,28]. sHSP activity is regulated at the level of the oligomeric ensemble by balancing between an inactive and active conformation [29–31]. 2.2. HSP40 HSP40, encoded by DNAJ genes, is the largest chaperone family containing 49 members that function in the cytosol or mitochondria [32,33]. All members of the family contain the conserved J domain usually present in the N-terminal region [34]. There are additional conserved regions, that are used to categorize the HSP40 proteins into three groups: Type 1 proteins (DNAJA) contain a J domain, a Gly/Phe-rich region, and cysteine-rich region with four zinc-finger motif repeats; Type 2 proteins (DNAJB) contain a J domain and a Gly/Phe-rich region; and Type 3 proteins (DNAJC) contain only a J domain [35–37]. HSP40 members primarily function as HSP70 co-chaperones [32]. HSP40 ATPase activity is essential for HSP70 protein activity as ATP hydrolysis converts HSP70 from an open state to Gastrointest. Disord. 2019, 1 41 a close state [38]. In addition to its role with HSP70, HSP40 performs typical chaperone functions such asGastrointest. protein Disord. folding/unfolding, 2018, 1, x FOR PEER translocation, REVIEW and degradation. 3 of 18 Figure 1.1. MajorMajor domainsdomains forfor eacheach ofof thethe HSPHSP families.families. NTD,NTD, N-terminalN-terminal domain;domain; ACD,ACD, αα-crystallin-crystallin domain; CTD, C-terminalC-terminal domain;domain; JD,JD, JJ domain;domain; G/FG/F region,region, Gly/Phe-richGly/Phe-rich region; C-rich region, cysteine-rich region;region; E1/2,E1/2, equatorial regionregion 1/2;1/2; I1/2, intermediate intermediate region region 1/2; AD, AD, apical domain; SBD, substrate-binding domain;domain; ABD,ABD, ATP-bindingATP-binding domain.domain. 2.3.2.2. HSP60HSP40 HSP60HSP40, encoded is an essential by DNAJ mitochondrial genes, is the largest chaperonin chaperone encoded family by containing the chromosomal 49 members gene that HSPD1function[32 in,39 the,40 cytosol]. Most informationor mitochondria on HSP60 [32,33]. structure All members is based of on the studies family of thecontain prokaryotic the conserved homolog, J GroEL,domain which usually has present three structural in the N-terminal domains: region apical (A),[34]. intermediateThere are additional (I1/2) and conserved equatorial regions, (E1/2) [that41]. Asare aused mitochondrial to categorize protein, the HSP40 HSP60 proteins catalyzes into the three folding groups: of matrix Type proteins 1 proteins and maintains(DNAJA) proteinscontain a in J andomain, unfolded a Gly/Phe-rich state to channel region, them and across cysteine-rich the inner region membrane with four for import zinc-finger or export motif [42 repeats;,43]. HSP60 Type is2 proteins (DNAJB) contain a J domain and a Gly/Phe-rich region; and Type 3 proteins (DNAJC) contain only a J domain [35–37]. HSP40 members primarily function as HSP70 co-chaperones [32]. HSP40 ATPase activity is essential for HSP70 protein activity as ATP hydrolysis converts HSP70 from an open state to a close state
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