Inflamm. Res. (2017) 66:209–216 DOI 10.1007/s00011-016-0995-1 Inflammation Research REVIEW The biological function and significance of CD74 in immune diseases 1,2 3 4 1,2 Huiting Su • Ning Na • Xiaodong Zhang • Yong Zhao Received: 18 August 2016 / Accepted: 30 September 2016 / Published online: 17 October 2016 Ó Springer International Publishing 2016 Abstract CD74 (MHC class II invariant chain, Ii) is a non- CD74 plays important roles in many inflammatory dis- polymorphic type II transmembrane glycoprotein. It is eases, such as liver fibrosis, type I diabetes, systemic lupus clear that, in addition to be an MHC class II chaperone, erythematosus, and Alzheimer disease. In this study, we CD74 has a diversity of biological functions in physio- will focus on the immunological functions of CD74 logical and pathological situations. CD74 also participates molecules and its roles in immune-relevant disorders. in other non-MHC II protein trafficking, such as angio- tensin II type I receptor. In addition, CD74 is a cell Keywords CD74 Á MIF Á Inflammation Á Innate immunity membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopachrome tautomerase (D- DT/MIF-2) and bacterial proteins. CD74 also regulates Introduction T-cell and B-cell developments, dendritic cell (DC) motility, macrophage inflammation, and thymic selection. CD74 (MHC class II invariant chain, Ii) is a non-poly- The activation of receptor complex CD74/CD44 may lead morphic type II transmembrane glycoprotein. It was to multiple intracellular signal pathways, such as the acti- initially identified to act mainly as an MHC class II vation of the extracellular signal regulated kinase (ERK) 1 chaperone. However, it is clear that CD74 has a much wide and 2, the PI3K-Akt signal transduction cascade, NFjB, range of biological functions in physiological and patho- and the AMP-activated protein kinase (AMPK) pathway. logical situations in addition to its regulatory roles on cell surface MHC II expression [1, 2]. CD74 also participates in other non-MHC II protein trafficking. Importantly, CD74 Responsible Editor: John Di Battista. molecule is a cell membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopa- & Xiaodong Zhang [email protected] chrome tautomerase (D-DT/MIF-2), and bacterial proteins that also behave as an accessory signaling molecule, which & Yong Zhao [email protected] undergoes regulated intramembrane proteolysis (RIP) upon its ligand binding [1, 3–6]. In this study, we will focus on 1 Transplantation Biology Research Division, State Key the immunological functions of CD74 molecule and its Laboratory of Membrane Biology, Institute of Zoology, roles in immune disorders. Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing 100101, China 2 University of Chinese Academy of Sciences, Beijing, China The expression of CD74 in immune cells 3 Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China Mouse CD74 molecule has a short N-terminal cytoplasmic tail of 28 amino acid (aa), a 24-aa transmembrane region 4 Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, and an approximately150-aa luminal domain [7]. The Beijing 100020, China intracellular domain of CD74 molecule lacks homology 123 210 H. Su et al. with tyrosine or serine/threonine kinases, so CD74 likely The bio-functions of CD74 lacks intracellular signaling motifs, but it may signal through binding to signaling proteins [6]. Furthermore, it A wide range of biological functions of CD74 have been may undergo phosphorylation and regulate intramembrane described over the years [1, 2]. CD74 was initially identi- proteolysis (RIP) [6]. Splicing of the transcription products fied to function mainly as an MHC class II chaperone. of CD74 gene in mice generates two different isoforms, However, it later became clear that CD74 also participates p31 and p41. Human CD74 molecule has 29–46 NH2- in other non-MHC II protein trafficking. In addition, CD74 terminal intracytoplasmic residues, a 26-aa hydrophobic is a cell membrane receptor for MIF, D-dopachrome tau- transmembrane region, and a 160-aa extracytoplasmic tomerase (D-DT/MIF-2), and bacterial proteins, so that domain containing two N-linked carbohydrate chains CD74 also acts as an accessory signaling molecule which [8–10]. The most common isoform is 33 kDa (p33), but undergoes regulated intramembrane proteolysis (RIP) upon there are also p35, p41, and p43 isoforms in humans [11]. its ligand binding [3–6]. CD74 molecules are predominantly localized intracellu- CD74 molecule, as an MHC class II chaperone, directly larly and about 2–5 % resides on the monocyte cell surface associates with the MHC class II a and b chains in the independently of MHC class II expression [3]. The surface endoplasmic reticulum (ER) forming a complex, prevents half-life of CD74 molecule is less than 10 min in a human peptide binding in ER, promotes the exit of the complex B-cell line due to the rapid internalization, indicating that from ER, directs transport of the complex to the endosomal CD74 remains on the cell surface for a very short period compartments, and contributes to peptide editing in the [12]. MHC class II compartment [26, 27]. The class II-associated MHC class II-positive cells, including dendritic cells invariant chain peptide region of CD74 molecule lies in the (DCs), monocytes/macrophages, langerhans cells, B cells, binding groove of the MHC class II a and b heterodimer thymic epithelial cells, and gastric epithelial cells express and prevents binding of peptides prior to the arrival of the CD74 molecules on cell surface. In addition, CD74 is non-americ complex at the endosomal compartments expressed in a number of cell types independently of MHC where the digested exogenous antigenic proteins are loca- class II [13]. CD74 expression is increased in diverse tissue ted [1]. While CD74 molecule is degraded by proteases and injury disorders, such as heart ischemia–reperfusion injury, released from MHC class II molecules in endosomes, MHC Alzheimer disease, atherosclerotic plaques, toxin-induced class II molecules form dimers that bind antigenic peptides liver fibrosis, and a broad range of malignant cells [14–22]. and subsequently traffic to the cell surface for antigen Thus, CD74 may modulate tissue injury and homeostasis of presentation. Inhibition of CD74 phosphorylation greatly immune system and beyond. The expression of CD74 impairs the trafficking of newly synthesized MHC class II molecule may be used as an independent prognostic factor molecules to antigen processing compartments. CD74 for survival and therapeutic target in patients with malig- molecule is also required for an MHC class I endolysoso- nancy [18]. mal cross-presentation pathway [28]. The expression of CD74 molecule is regulated by mul- In addition to the essential role of CD74 molecules in tiple pathways. In immature DCs, the cytoplasmic domain antigen presentation pathway, CD74 also regulates traf- of CD74 molecule is exposed to the proteolytic activity of ficking of additional molecules, such as angiotensin II type caspases, such as caspase-1 and caspase-4. The degradation I receptor (AT1) (Table 1). CD74 directly associates with of CD74 molecule by caspases in immature DCs was AT1 early in the biosynthetic pathway, and impedes its inhibited upon treatment with nitric oxide (NO) donor. intracellular trafficking. Consequently, coexpression of Inducible nitric-oxide synthase (iNOS, NOS2) can directly CD74 molecules causes AT1 accumulation in the ER and interact with the cytoplasmic domain of CD74 and cat- AT1 proteasomal degradation [29]. The longer molecules alyzes the production of NO, which inhibits caspases and (p41 and p43 in humans) have a thyroglobulin type I protects CD74 from proteolytic degradation, promoting the domain that binds to and stabilizes cathepsin L, allowing cell surface expression of MHC class II molecules in accumulation of the resulting CD74-cathepsin L complex maturing DCs [23]. Thus, the increasing cell surface in the extracellular space [28]. localization of MHC class II molecules in maturing DCs is CD74 significantly regulates B-cell development, DC partially due to the increased CD74 protein expression motility, and thymic selection [30]. CD74 controls the caused by iNOS and NO. It was recently demonstrated that maturation of B cells through NF-jB p65/RelA homodimer intramembrane proteolysis of the final membrane-bound and its coactivator TAFII105 [6, 7]. Peripheral B-cell N-terminal fragment (NTF) of CD74 molecules is cat- homeostasis is disturbed by the accumulation of the alyzed by signal peptide peptidase-like 2a (SPPL2a) and unprocessed CD74 NTF in SPPL2a-deficient mice. The that this process is indispensable for the development and absence of SPPL2a at the protein level in human B cells function of B cells in mice [24, 25]. 123 The biological function and significance of CD74 in immune diseases 211 Table 1 A brief summary of the CD74 biological functions Ligand or partner molecule Function 1 MHC class I and II, AT1, cathepsins, NOS2 Regulation of protein trafficking, chaperone 2 MIF, D-DT/MIF-2, H. pylori urease B subunit Receptor (interactions with CD44 and CXCR2), accessory signaling molecule also promotes an accumulation of the CD74 NTF [24, 25]. T-cell proliferation and cytokine secretion [41, 42]. The Thus, SPPL2a may regulate B-cell development through antagonistic ability of MIF on the anti-inflammatory effects CD74-dependent manner in mice and humans. of glucocorticoids is observed in mouse models of exper- MIF is a key cytokine closely involved in autoimmune imental arthritis and acute respiratory distress syndrome and inflammatory diseases. MIF attracts and subsequently [43–45]. The underlying mechanisms for such antagonism retains activated immune cells from the periphery to the are not fully understood. MIF fails to change the gluco- inflamed tissues [31]. The biological effects of MIF are corticoid receptor expression and affinity [46], but it predominately mediated through its primary receptor, prolongs the activation of ERK and p38 MAP kinases, CD74 (Fig.