Yueping Qiu

and 5 more

IntroductionThe lysosomal degradation pathway of autophagy is a highly conserved mechanism in eukaryotic cells and play an important role in cellular, tissue and organismal homeostasis by removing dysfunctional organelles, intracellular bacterial and aggregated proteins selectively (Zaffagnini et al. , 2016). Autophagy can be activated by cellular stress such as starvation, hypoxia, oxidative stress, protein aggregation, endoplasmic reticulum (ER) stress and others, which triggers the cell survival process and thus provides energy to the cells when energy is consumed (Levineet al. , 2019). Thus, autophagy is generally considered to be a cell survival process and play an important role in the maintenance of cellular homeostasis.At present, it is divided into three categories according to the occurrence process: Macroautophagy (also termed autophagy), Microautophagy, and Chaperone-mediated autophagy (CMA), the following refers to the first category unless otherwise specified (Wen et al. , 2016). It is generally accepted that autophagy is a more selective process than originally expected. Autophagy can be divided into different types, according to the different autophagy substrates(also called cargo), for example, aggrephagy for protein aggregates, lysophagy for damaged lysosomes, mitophagy for mitochondria and xenophagy for intracellular bacterial. Conservatively, most of these different types of selective autophagy pathways use a common mechanism.Up to now, there are 34 Autophagy-related (ATG) genes that is discovered in yeast and 15 of which are “core” ATG genes that are commonly necessary to the different pathways of autophagy (Nakatogawa et al. , 2009). The autophagosome biogenesis process can be divided into four steps, the first is the nucleation and expansion of the phagophore, the second is the formation of autophagosome, the third is the autophagosome and lysosome fuse to form autolysosome, and the last is degrades the cargos by enzymes in lysosomes.It is also generally conceded that the trigger of autophagy results in ATGs recruitment, Unc-51-like kinase 1 (ULK1) complex (consisting of ULK1/2, ATG13, FIP200 and ATG101), to the phagophore assembly site (PAS), a specific subcellular location where the nucleation of phagophore to be triggered. Then a cup-shaped structure isolation membrane is formed from the different source of membrane including mitochondria, endoplasmic reticulum. Meanwhile, ‘eat-me’ signals are necessary to cargo to be selectively recognized by several autophagy receptors that link the cargo to the autophagic membrane via their light chain 3 (LC3)-interacting region (LIR) by Atg8. The most primarily ‘eat-me’ signals is ubiquitin (Ub) chains. Atg8 is a ubiquitin-like protein, can be tightly bound to the autophagic membranes when it was cleaved at its C-termini by the ATG4 pro- teases to expose a C-terminal glycine producing the form I of the ATG8 molecule, and then conjugated to PE and being an PE-conjugated form II of ATG8 proteins. Yeast only owns the one kind of Atg8 protein, while mammals have at least seven if not more ATG8 proteins that can be fell into two subfamilies containing not less than three MAP1 light chain 3 (LC3A, B and C) and four gamma-aminobutyrate receptor-associated protein (GABARAP) and GABARAP-like proteins (ATG8L/GEC-1/GABARAPL1, GATE-16/GABARAPL2 and GABARAPL3) (Xin et al. , 2001; He et al. , 2003).Many proteins have been identified as autophagy receptors that can recognize the ‘eat-me’ signals of cargos, and the classic and wildly accepted autophagy receptors including p62, OPTN, TAX1BP1, NDP52 (Pohl et al. , 2019). Each of these receptors contains LC3 interacting regions (LIRs) that facilitate their interaction with LC3-like molecules on the autophagosome (Wildet al. , 2011; Katsuragi et al. , 2015; Tumbarello et al. , 2015).Furthermore, there is a clear etiological link between gene mutations that control autophagy and human diseases (especially neurodegenerative diseases, inflammatory diseases, and cancer) (Levine et al. , 2019). These diseases are largely untreatable and have no target for intervention that needed an interventional therapeutic target and an interventional target drug. Therefore, these genes that play an important role in autophagy have the opportunity to be the candidate therapeutic targets for these diseases. As we introduced above, the autophagy related genes mainly including Atgs and autophagy receptors. Among them, OPTN is well-documented to have a strong relationship with several disease, for example, neurodegenerative diseases, cancer, inflammatory diseases,etc . (Liu et al. , 2018; Weil et al. , 2018).OPTN is a conservative protein in many species, including human, macaques, rats, pigs, and bovine and is widely in liver, heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, retina, optic nerve blood vessels and so on. OPTN was identified as a negative regulator of NF-κB that competitively binds ubiquitin with NEMO (NF-κB essential modulator) (Zhu et al. , 2007), and an autophagy receptor that connect the ubiquitinated autophagy substrate and LC3-positive autophagosome membrane (Wildet al. , 2011). What’s more, OPTN is also an autophagy inducer that induce autophagic process upon overexpression (Ying et al. , 2016). Breakthrough has been made in comprehending the molecular mechanisms of OPTN in autophagy since 2011. OPTN is an important autophagy adaptor, participate in almost every step of the autophagy process and not just as a autophagy receptor. But the existing review neither clearly clarify this point neither sort out the existing literature lucidly.Over the past decade of studies, OPTN has been involved in many biological process, and its role as autophagy receptor is a breakthrough finding which caught scientists attention in recent years. Contemporary, OPTN was closely associated with some incurable disease in human beings, such as ALS, glaucoma, Paget’s disease, Crohn’s disease, and recently cancer and diabetic nephropathy. However, the relationship between OPTN and these disease has not been well revealed and clarified. This review discusses the biological functions of OPTN in the process of autophagy and the perspective of autophagic mechanism that OPTN involved in several human diseases.The Protein Structure and Cellular Function of OPTNOptineurin(OPTN) was first identified by a yeast two-hybrid screening in order to find interacting proteins of Ad E3 14.7-kDa protein (E3-14.7K) that inhibit TNF-α functions (Li et al. , 1998), and named as FIP-2(14.7K-interacting protein). Then Klaus et al . using “Data base searching” found a NEMO-related protein that shows a strong homology to NEMO, which is the second time that OPTN come into the sight of scientists and name NRP (the first letter of each word in “NEMO-related protein”) (Schwamborn et al. , 2000). After then, more and more studies have sprung up like mushrooms that uncovering the enigma of OPTN in structure of protein, biological function and etiological link in disease.The human OPTN protein contains 577 amino acids and is a 74kD scaffold protein contains several structural domains that endow its multiple abilities. And the mouseOptn gene codes for a 584–amino acid protein (67 kD) which is 78% identical to human OPTN (Rezaie et al. , 2005). The public databases contain partial or complete sequences of OPTN homologues of macaques, rats, pigs, and bovine, all of which show a great extent of similarity to human OPTN, which means OPTN is a conserved gene that play an important role in vital activity. OPTN contains several structural domains and is consists of the structures including CC (coiled-coil) domain, LZ (leucine zipper) domain, LIR (LC3 interacting region) domain, UBAN (ubiquitin-binding domain (UBD) of ABIN proteins and NEMO) domain, ZF (zinc finger) domain. The LIR domain and UBD domain play an important role in autophagy and is the foundation of OPTN to function as an autophagy receptor. In detail, the LIR domain is the location that binding LC3II and the UBD domain is the place where attach the ubiquitinated cargos. The LC3II is an PE-conjugated form II of ATG8 proteins that can tightly bound to the autophagic membranes. So that, cargos are enclosed by autophagic membranes and turn into autophagosome and then degraded in autolysosome.Many biological function of OPTN was reported so far. Firstly, Tayebeh et al. using immunocytochemistry to found the intracellular localization of OPTN and observed the colocalization with the Golgi apparatus (Rezaieet al. , 2002). A deeper study bring this colocalization to light, OPTN plays a vital role in the maintenance of Golgi integrity (Parket al. , 2006).Secondly, OPTN shows strong homology with NEMO, and was identified as a negative regulator of NF-κB that competitively binds ubiquitin with NEMO, thus it may have role in NF-κB signaling regulation. Thirdly, Wild et al. fully proved the specific interactions between OPTN and LC3/GABARAP proteins by pull-down assays in MCF-7 cells, yeast two-hybrid transformations, and purified proteins in vitro (Wild et al. , 2011). The vital role of OPTN in autophagy has attracted greater attention in the last ten years.