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While the ubiquitin\u2013proteasome system efficiently removes many soluble misfolded proteins, large or persistent assemblies often require the autophagy\u2013lysosome pathway for their degradation. In the present mini-review, we summarize our knowledge of aggrephagy, the selective clearance of protein aggregates by autophagy, and discuss two recent manuscripts that argue that some aggregates must be primed for autophagosomal degradation, through chaperone-mediated remodeling. Aggrephagy substrates are defined by aggregate architecture, biophysical state, surface accessibility, and the physical constraints of membrane capture. These features help to explain why recruitment of selective autophagy receptors is necessary yet insufficient for clearance. Receptor clustering is required to concentrate early autophagy factors to establish initiation hubs, but successful degradation often requires upstream generation of smaller \u2018aggrephagy-competent\u2019 cargo units, which contain autophagy receptor clusters that successfully initiate autophagosome formation. Recent work supports a model in which larger aggregates are cleared through stepwise degradation enabled by prior remodeling steps that involve p97\/VCP-driven disintegration or a chaperone module (DNAJB6\u2013HSP70\u2013HSP110) cooperating with the proteasomal 19S regulatory particle.<\/jats:p>","DOI":"10.1042\/bst20250460","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:48:26Z","timestamp":1782121706000},"page":"803-814","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Small bites for big problems: stepwise aggregate degradation by autophagy"],"prefix":"10.1042","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-3016","authenticated-orcid":false,"given":"Mark\u00a0S.","family":"Hipp","sequence":"first","affiliation":[{"name":"1Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"},{"name":"2School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0049-7961","authenticated-orcid":false,"given":"Mario","family":"Mauthe","sequence":"additional","affiliation":[{"name":"1Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"2026062205481567700_B1","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","article-title":"Hallmarks of neurodegenerative diseases","volume":"186","author":"Wilson","year":"2023","journal-title":"Cell"},{"key":"2026062205481567700_B2","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1038\/nm1066","article-title":"Protein aggregation and neurodegenerative disease","volume":"10","author":"Ross","year":"2004","journal-title":"Nat. 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