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The Pathways Underlying the Multiple Roles of P62 in Inflammation And biomedicines Review The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer Paulina Hennig 1,2 , Gabriele Fenini 1,2 , Michela Di Filippo 1,2, Tugay Karakaya 1,2 and Hans-Dietmar Beer 1,2,* 1 Department of Dermatology, University Hospital Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland; [email protected] (P.H.); [email protected] (G.F.); Michela.Difi[email protected] (M.D.F.); [email protected] (T.K.) 2 Faculty of Medicine, University of Zurich, CH-8032 Zurich, Switzerland * Correspondence: [email protected] Abstract: p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. Via binding of ubiquitin chains, p62 acts in an anti-inflammatory manner as an adaptor for the auto-, xeno-, and mitophagy-dependent degradation of proteins, pathogens, and mitochondria. Furthermore, p62 is a negative regulator of inflammasome complexes. The transcription factor Nrf2 regulates expression of a bundle of ROS detoxifying genes. p62 activates Nrf2 by interaction with and autophagosomal degradation of the Nrf2 inhibitor Keap1. Moreover, p62 activates mTOR, the central kinase of the mTORC1 sensor complex that controls cell proliferation and differentiation. Through different mechanisms, p62 acts as a positive regulator of the transcription factor NF-κB, a central player in inflammation and cancer development. Therefore, p62 represents not only a cargo receptor for autophagy, but also a central Citation: Hennig, P.; Fenini, G.; Di signaling hub, linking several important pro- and anti-inflammatory pathways. This review aims to Filippo, M.; Karakaya, T.; Beer, H.-D. summarize knowledge about the molecular mechanisms underlying the roles of p62 in health and The Pathways Underlying the disease. In particular, different types of tumors are characterized by deregulated levels of p62. The Multiple Roles of p62 in Inflammation elucidation of how p62 contributes to inflammation and cancer progression at the molecular level and Cancer. Biomedicines 2021, 9, 707. might promote the development of novel therapeutic strategies. https://doi.org/10.3390/biomedicines 9070707 Keywords: p62; autophagy; inflammasomes; Nrf2/Keap1; NF-κB; mTORC1; inflammation; cancer Academic Editor: Juan Gambini Received: 19 May 2021 1. Introduction Accepted: 18 June 2021 Published: 22 June 2021 SQSTM1 (sequestosome 1), the gene coding for the p62 protein, spans about 16 kb and is located on chromosome 5 [1,2]. It is widely expressed and contains eight exons 0 0 Publisher’s Note: MDPI stays neutral with a short 5 UTR (untranslated region) and an unusually long 3 UTR [3,4] (Figure1) . with regard to jurisdictional claims in In humans, due to alternative splicing, SQSTM1 gives rise to two different isoforms. published maps and institutional affil- Isoform 1 represents the full-length p62 protein with 440 amino acids, whereas isoform iations. 2 lacks 84 amino acids at the amino terminus in the PB1 domain [5–7]. The expression of SQSTM1 is stress-associated and induced by the transcription factors Nrf2, NF-κB, and MiT/TFE [8–10]. Apart from their roles in melanocytes, members of the MiT/TFE (microphthalmia/transcription factor E) family of helix-loop-helix transcription factors are Copyright: © 2021 by the authors. activated by different types of internal and external stresses and also in cancer [11] (for κ Licensee MDPI, Basel, Switzerland. Nrf2 see Section 4.2 and for NF- B Section 4.4). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 707. https://doi.org/10.3390/biomedicines9070707 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 707 2 of 19 Biomedicines 2021, 9, 707 2 of 19 FigureFigure 1. 1. StructureStructure of of SQSTM1 and p62. Domain architecture of p62, posttranslationalposttranslational modifications,modifications, binding/modifying proteinsproteins and and pathways pathways regulated regulated by p62. p62. The The PB1 PB1 domain domain medi mediatesates oligomerization oligomerization and and activa activationtion of of p62, p62, UBA-mediated UBA-mediated dimerizationdimerization holds holds p62 p62 inactive. inactive. For For phase phase separation, separation, the the PB1 PB1 and and UBA UBA domains domains are are required. required. The The role role of of p62 p62 as as a a cargo cargo receptorreceptor in in autophagy autophagy is is mediated mediated by by the the LIR LIR motif, motif, link linkinging it it to to LC3 LC3 on autophagosom autophagosomes,es, and and the the UBA UBA domain, domain, which which bindsbinds to ubiquitinated cargos.cargos. UponUpon phosphorylation phosphorylation at at Ser349, Ser349, the the KIR KIR motif motif interacts interacts with with Keap1, Keap1, thereby thereby liberating liberating Nrf2 Nrf2and inducingand inducing Nrf2 Nrf2 target target gene gene expression. expression. When When Raptor Raptor binds binds to p62, to p62, mTOR mTOR is activated is activated inducing inducing metabolic metabolic pathways. path- ways.Binding Binding of RIP1 of RIP1 to the to ZZ the or ZZ TRAF6 or TRAF6 to the to the TB motifTB motif supports supports activation activation of of NF- NF-κB.κB. Cleavage Cleavage after after Asp329 Asp329 by by caspase-8 caspase- 8 (casp-8) or caspase-1 (casp-1) generates an amino terminal fragment of p62 activating mTOR. Disulfide bond formation (casp-8) or caspase-1 (casp-1) generates an amino terminal fragment of p62 activating mTOR. Disulfide bond formation involving Cys105 or Cys113 as well as binding of vault RNA1-1 via the ZZ motif supports autophagy. Please see in the involving Cys105 or Cys113 as well as binding of vault RNA1-1 via the ZZ motif supports autophagy. Please see in the text text for details. Abbreviations: Ac: acetylation, dAc: de-acetylation, C: Cys, D: Asp, K: Lys, KIR: Keap1-interacting region, LIR:for details. LC3-interacting Abbreviations: region, Ac: NES: acetylation, nuclear export dAc: de-acetylation, signal/sequence, C: Cys, NLS: D: nuclear Asp, K: localization Lys, KIR: Keap1-interacting signal/sequence, region,PB1: Phox LIR: andLC3-interacting Bem1p, S: Ser, region, T: Thr, NES: TB: nuclearTRAF6-binding export signal/sequence, domain, UBA: ubiquitin-as NLS: nuclearsociated, localization ZZ: Zinc signal/sequence, finger, [1,12–14]. PB1: Phox and Bem1p, S: Ser, T: Thr, TB: TRAF6-binding domain, UBA: ubiquitin-associated, ZZ: Zinc finger, [1,12–14]. Deregulated SQSTM1 expression is associated with several human diseases [12,15]. MissenseDeregulated mutationsSQSTM1 of SQSTM1expression cause ALS is associated (amyotrophic with severallateral sclerosis), human diseases PDB (Paget’s [12,15]. SQSTM1 diseaseMissense of bone) mutations or FTLD of (frontotemporalcause ALS lobar (amyotrophic degeneration) lateral [16]. sclerosis), ALS is a PDBneurodegen- (Paget’s disease of bone) or FTLD (frontotemporal lobar degeneration) [16]. ALS is a neurode- erative disease of motor neurons. The role of p62 in ALS is most likely defined by its au- generative disease of motor neurons. The role of p62 in ALS is most likely defined by tophagy-dependent requirement for proteostasis [17], the dynamic regulation of a func- its autophagy-dependent requirement for proteostasis [17], the dynamic regulation of a tional proteome [18]. Similarly, FTLD is caused by proteotoxic stress-induced neurotoxi- functional proteome [18]. Similarly, FTLD is caused by proteotoxic stress-induced neu- city due to the absence of functional SQSTM1 expression [19]. In PDB, a chronic progres- rotoxicity due to the absence of functional SQSTM1 expression [19]. In PDB, a chronic sive skeletal disorder, p62 mutations induce activation of osteoclasts in a non-physiologi- progressive skeletal disorder, p62 mutations induce activation of osteoclasts in a non- cal manner resulting in increased and deregulated bone turnover [20,21]. Other neuro- physiological manner resulting in increased and deregulated bone turnover [20,21]. Other degenerative diseases, such as Parkinson’s disease and Huntington’s disease, are also neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease, are characterized by low levels of p62 [22]. In contrast, numerous types of cancer exhibit in- also characterized by low levels of p62 [22]. In contrast, numerous types of cancer exhibit creased amounts of p62 in the tumor cells, including hepatocellular carcinoma (HCC, see increased amounts of p62 in the tumor cells, including hepatocellular carcinoma (HCC, Sectionsee Section 5, ovarian,5, ovarian, breast, breast, lung, lung, or pancreatic or pancreatic cancer cancer [1,5,23–28]. [ 1,5,23 In–28 these]. In cells, these high cells, levels high oflevels p62 cause of p62 Nrf2 cause (Section Nrf2 (Section 4.2), mTORC1 4.2), mTORC1 (Section (Section 4.3), or/and 4.3), or/andNF-κB (Section NF-κB (Section4.4) activa- 4.4) tion,activation, which whichfavors favorsthe development the development and proliferation and proliferation of cancer of cancer cells. Interestingly, cells. Interestingly, high levelshigh levelsof p62-positive of p62-positive inclusion inclusion bodies, bodies, termed termed Mallory–Denk Mallory–Denk bodies, bodies, are are frequently frequently foundfound
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