Autophagy receptors

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Autophagy receptors

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Autophagy receptors are important for protein homeostasis, by regulating the clearance of protein aggregates, pathogens and the turnover of a wide range of cargo proteins, via the autophagosome-lysosome pathway, by ubiquitin-dependent and -independent mechanisms [3]. Their activity is modulated by protein modifications such as phosphorylation and ubiquitination. Some autophagy receptors have been associated with neurodegenerative diseases [2,10].

Targets

Targets of relevance to immunopharmacology are highlighted in blue

sequestosome 1 Show summary »« Hide summary

Target Id

3213

Nomenclature

sequestosome 1

Previous and unofficial names

autophagy receptor p62 | p62

Genes

SQSTM1 (Hs), Sqstm1 (Mm), Sqstm1 (Rn)

Ensembl ID

ENSG00000161011 (Hs), ENSMUSG00000015837 (Mm), ENSRNOG00000003147 (Rn)

UniProtKB AC

Q13501 (Hs), Q64337 (Mm)

Ligands

oroxylin A (Inhibition) pK_d 5.9 (Disrupts SQSTM1/PKCζ interaction)

Agonists

YTK-2205 (Activation) [4]

Comment

Sequestosome 1 (widely referred to as p62) is the most studied 'selective' autophagy receptor. It facilitates autophagy of certain protein aggregates (aggrephagy), pathogens (xenophagy) and enzymes (zymophagy). Kinases that phosphorylate sequestosome 1 include ULK1 [5], TBK1 [8],CK2 [6] and p38δ. It is ubiquitinated by the E3 ubiquitin transferase TRIM21 [2,7]. These protein modifications regulate sequestosome 1's activity and selectivity for cargo proteins. Genetic variants in SQSTM1 are associated with amyotrophic lateral sclerosis (ALS; NMD)/frontotemporal lobar degeneration (FTLD) [9,11] and Alzheimer's disease [1].

References

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1. Cuyvers E, van der Zee J, Bettens K, Engelborghs S, Vandenbulcke M, Robberecht C, Dillen L, Merlin C, Geerts N, Graff C et al.. (2015) Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study. Neurobiol Aging, 36 (5): 2005.e15-22. [PMID:25796131]

2. Deng Z, Purtell K, Lachance V, Wold MS, Chen S, Yue Z. (2017) Autophagy Receptors and Neurodegenerative Diseases. Trends Cell Biol, 27 (7): 491-504. [PMID:28169082]

3. Khaminets A, Behl C, Dikic I. (2016) Ubiquitin-Dependent And Independent Signals In Selective Autophagy. Trends Cell Biol, 26 (1): 6-16. [PMID:26437584]

4. Kwon YT, Ji CH, Ganipisetti S, Kim HY, Mun SR, Jung CH, Jung EJ, Sung KE. (2021) Novel p62 ligand compound, and composition for preventing, ameliorating or treating proteinopathies compring the same. Patent number: US20210163399A1. Assignee: PROTECH CO Ltd. Priority date: 24/07/2018. Publication date: 03/06/2021.

5. Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, Komatsu M, Oh YJ, Zhao Y, Yue Z. (2015) Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet, 11 (2): e1004987. [PMID:25723488]

6. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. (2011) Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell, 44 (2): 279-89. [PMID:22017874]

7. Pan JA, Sun Y, Jiang YP, Bott AJ, Jaber N, Dou Z, Yang B, Chen JS, Catanzaro JM, Du C et al.. (2016) TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Mol Cell, 61 (5): 720-733. [PMID:26942676]

8. Pilli M, Arko-Mensah J, Ponpuak M, Roberts E, Master S, Mandell MA, Dupont N, Ornatowski W, Jiang S, Bradfute SB et al.. (2012) TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity, 37 (2): 223-34. [PMID:22921120]

9. Rea SL, Majcher V, Searle MS, Layfield R. (2014) SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD. Exp Cell Res, 325 (1): 27-37. [PMID:24486447]

10. Roşianu F, Mihaylov SR, Eder N, Martiniuc A, Claxton S, Flynn HR, Jalal S, Domart MC, Collinson L, Skehel M et al.. (2023) Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration. Life Sci Alliance, 6 (2). [PMID:36446521]

11. van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, Matěj R, Vandenbulcke M, Sieben A, Dermaut B et al.. (2014) Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta Neuropathol, 128 (3): 397-410. [PMID:24899140]

How to cite this family page

Database page citation:

Autophagy receptors. Accessed on 17/05/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1073.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Spedding M, Cidlowski JA, Fabbro D, Davenport AP, Striessnig J, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. Br J Pharmacol. 180 Suppl 2:S1-22.