Autophagy is an evolutionary conserved self-cannibalistic pathway that leads to the degradation of bulk cytoplasm (macroautophagy) in order to generate energy and to maintain cell homeostasis (1). However, researchers are increasingly appreciating that receptors specifically guide autophagic degradation as exemplified by the removal of damaged organelles [e.g., mitophagy of mitochondria, ER-phagy of endoplasmic reticulum (ER), pexophagy of peroxisomes], bacteria (xenophagy), lipid droplets (lipophagy), protein aggregates (aggrephagy), and other cytosolic constituents (2, 3). This rather selective autophagic process may be controlled by Optineurin (OPTN) besides other autophagy receptors including p62/SQSTM1, NBR1, CALCOCO2/NDP52, and TAX1BP1 (3, 4). These receptors recognize ubiquitinated cargo via their ubiquitin-binding domains (UBA, UBZ or UBAN) and tether it to the autophagosomal membranes by their LC3-interacting regions (LIRs) (5). However, OPTN does not only guide selective autophagy but also controls tumor necrosis factor (TNF), nuclear factor κB (NF-κB), and type I interferon (IFN) signaling (6–8). OPTN has been implicated in a variety of human diseases including glaucoma (9), amyotrophic lateral sclerosis (10, 11), Paget’s disease (12, 13), and recently, inflammatory bowel disease (IBD) (14, 15). IBD comprise a spectrum of complex diseases that affect the gastrointestinal tract and organs beyond the intestine (e.g., eye, skin, joints). IBD is clinically distinguished into two major phenotypes: ulcerative colitis (UC) and Crohn’s disease (CD). Although these two diseases share some genetic risk they are considered separate disease entities due to their localization, clinical presentation and response to therapy (16). The pathophysiology of these diseases involves environmental factors and their impact on the intestinal microbiota which may orchestrate a chronic remittent form of inflammation in genetically susceptible hosts (17–19). Genetic variation in the autophagy gene ATG16L1 has been linked to CD (20, 21) which leads to an impaired autophagic response due to caspase 3-mediated cleavage of the mutant ATG16L1 variant (22). Impaired autophagy function especially in intestinal epithelial cells results in the susceptibility to small and large intestinal inflammation (23–27). As such, it is conceivable that the selective autophagy receptor OPTN may regulate inflammatory processes in the intestine. Evidence for the regulation and function of OPTN in intestinal inflammation and specifically IBD is covered in this review.

The gene encoding OPTN is evolutionary conserved and expressed in most tissues of the human body (28). OPTN was initially discovered in 1998 in a yeast two-hybrid screen as a binding partner of the adenovirus protein E3-14.7K (early region 3 of group C human adenoviruses 14.7 kDa), and was thereafter named as FIP-2 (for 14.7 kDa interacting protein) (28). Later, this gene was identified to have a strong homology with NEMO (NF-κB essential modulator) and was subsequently denoted as NEMO-related protein (29). But it also became known as transcription factor IIIA-interacting protein, Huntingtin-interacting protein 7, and Huntingtin yeast partner L (30). Eventually, the multifunctional protein was renamed to OPTN (“optic neuropathy inducing”), as it was found to play a major neuroprotective role and mutations in this gene were shown to be causative for the development of primary open-angle glaucoma, a leading cause of blindness (9).

The human OPTN gene is located at chromosome 10 and consists of three non-coding exons in the 5′UTR and 13 exons that encode a 577 amino acid protein with a size of 66 kDa. The mouse Optn gene is located at chromosome 2 and also contains 13 exons, which encodes a full-length protein of similar size that shows 78% sequence similarity to the human protein (6, 30). The OPTN protein consists of several functional domains including a basic leucine zipper motif (bZIP), a microtubule-associated protein 1 light-chain LIR, a ubiquitin-binding domain (UBAN), multiple coiled-coil motifs as well as a ubiquitin-binding zinc-finger domain at the C-terminus (6). Notably, NEMO, a central regulator of NF-κB activation shares 53% similarity with OPTN and only lacks a fragment of 166 amino acids at the N-terminal region containing a putative leucine zipper domain (30). However, despite this similarity, OPTN is (unlike NEMO) not a regulatory subunit of the IκB kinase (IKK) complex that is essential for NF-κB activation (29). OPTN was shown to block the ability of NEMO to bind ubiquitinated receptor-interacting protein kinase 1 (RIPK1), which resulted in a suppression of TNF-induced NF-κB signaling (8). Similarly, OPTN also inhibits NF-κB signaling through interaction with CYLD that leads to deubiquitination of NEMO and RIPK1 (31). Notably, OPTN is induced by TNF receptor signaling and can thus function as a negative-feedback regulator for NF-κB (32). As such, OPTN negatively regulates TNFα-mediated NF-κB signaling which is critically involved in the regulation of immune responses and cell death signaling. In contrast, in vivo experiments using Optn knock-out and Optn^470T knock-in mice suggest that OPTN plays no role in the regulation of NF-κB signaling (33, 34).

Furthermore, OPTN was shown to be regulated by and control type I IFN responses (7, 29, 35). Production of type I IFNs is the primary response to bacterial and viral infections (36). Specifically, upon recognition of pathogen-associated molecular patterns by toll-like receptors or RIG-I-like receptors, IFN regulatory factor 3 (IRF3) becomes phosphorylated by TANK-binding kinase 1 (TBK1) and translocates to the nucleus, which leads to the transcription of type I IFN response genes (7). OPTN binds to TBK1 to support IRF3 activation and production of type I IFNs (34). In contrast to this notion, however, OPTN was shown to suppress virus-induced IRF3 signaling (37).

More recently, OPTN was identified as a selective autophagy receptor required for autophagic clearance of Salmonella enterica (38), removal of damaged mitochondria (39) and degradation of protein clusters at the ER (24). Selective autophagy receptors, i.e., OPTN, NDP52, p62, and TAX1BP1 recognize ubiquitinated cargo and link it to the autophagosomal membrane (3). Before autophagic clearance of the ubiquitinated cargo, TBK1 activates OPTN by phosphorylation in order to enhance its binding capacity to LC3, a conjugate of the autophagosomal membrane (38, 40). A similar mechanism has for example been demonstrated for mitophagy (41). Only recently, a mechanistic link between OPTN and autophagy has been provided. Bansal and colleagues demonstrated an interaction of OPTN with the core autophagy machinery forming around ATG16L1. More specifically, the authors demonstrated that OPTN was required for the recruitment of the ATG12/ATG5/ATG16L1 complex to phagophores for autophagosomal elongation in starvation-induced autophagy (42).

Optineurin controls autophagic processes by selectively targeting ubiquitinated molecules for autophagic degradation (3, 4). A direct interaction of OPTN with IRE1α in intestinal epithelial cells and the requirement of OPTN for the removal of this inflammatory signaling hub may set a basis for our understanding of how autophagy can resolve ER stress-induced inflammation. We suggest that IRE1α is targeted by OPTN for autophagosomal degradation under conditions of ER stress to restrain IRE1α-mediated danger signaling and inflammation (24). Similarly, ER-phagy of stressed ER membranes also leads to the resolution of ER stress (56) which suggests once more that a tight control of the ER is indispensable for cellular homeostasis (57–61). Furthermore, OPTN is required to target a critical autophagy hub containing ATG16L1 to the forming phagophore (42). However, we acknowledge that distinct mechanisms other than selective autophagy may control IRE1α activity and an inflammatory threshold (62).

Understanding the selectivity of OPTN-mediated autophagy would be highly informative. For example, definition of an unbiased OPTN interactome could help to understand two major biological functions of OPTN (i.e., selective autophagy and regulation of inflammatory pathways) and to define their relationship in health and disease. More specifically, it may be critical to discriminate OPTN-mediated autophagy functions from those that are independent of autophagy as it currently unclear how they are interconnected. Some literature would support the notion that receptors of selective autophagy are critically involved in inflammatory processes (63) similar to a genetic variant in NDP52 with CD (64). Furthermore, autophagy receptors may control microbial dissemination (65, 66), a concept that becomes increasingly relevant in dysbiotic situations as seen in IBD (67). Reduction of OPTN expression in macrophages of some CD patients may not just result in diminished cytokine secretion upon bacterial infections (15), but may also lead to a decreased autophagic containment of pathogens (or commensals) and degradation of inflammatory molecules as exemplified for IRE1α in Paneth cells (24). However, it may well be that microbial control and ER stress are interrelated pathways (68). The impact of these observations in IBD deserve further attention and direct evidence for the regulation and function of OPTN in epithelial cells of CD patients is eagerly awaited.

In case of OPTN-mediated autophagy, we are only beginning to appreciate a role in intestinal inflammatory disease processes. However, we propose broad implications for OPTN in ER stress-related diseases within and beyond the intestine (24, 69–71). A driving force (besides genetic variation and environmental cues) may be cellular senescence with a declining capacity of the UPR during aging (72).

Evidence accumulates for a role of OPTN in disease processes within and beyond the intestine. Direct evidence for a role of OPTN in CD is limited. However a concept arises, in which OPTN is required for the removal of inflammatory molecules from the ER and invading bacteria (14, 15, 24), which may be governed by OPTN-mediated selective autophagy. As such, OPTN emerges as a critical link between ER disturbances and the resolution by autophagy (24). This observation is of note as ER stress is commonly observed in IBD patients and especially those harboring prominent genetic risk factors (e.g., ATG16L1 and NOD2) (22, 73, 74), which reflects one facet in this complex inflammatory condition (17, 19). Pharmacologic targeting of autophagy may indeed be beneficial in IBD which could depend on the ability of the host to launch an appropriate autophagic response (75). Moreover, clinically established drugs may exert their beneficial effects through modulation of autophagy (75). As such, understanding the biology of OPTN in CD may help to establish or guide future therapies.

MT and TA contributed equally to this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.