Microaggrephagy: an ESCRT-I-PTPN23-dependent pathway for MAPT/tau aggregate clearance

The clearance mechanisms for ubiquitinated protein aggregates, such as MAPT/tau in neurodegenerative diseases, remain incompletely understood, particularly regarding the role of microautophagy. To identify mediators of this process, we performed an unbiased genome-wide CRISPR knockout screen using cells propagating MAPT/tau repeat domain (MAPT/tauRD) aggregates. This screen identified the ESCRT-I complex and the accessory protein PTPN23 as essential for the clearance of ubiquitinated MAPT/tauRD aggregates via a microautophagy-dependent pathway, operating independently of macroautophagy and chaperone-mediated autophagy. We designate this pathway "microaggrephagy". Mechanistically, microaggrephagy involves the recognition of polyubiquitinated aggregates by the ESCRT-I subunit TSG101, with PTPN23 acting as an adaptor bridging ESCRT-I and ESCRT-III to facilitate microautophagic engulfment. Furthermore, a disease-associated mutation in the ESCRT-I component UBAP1 disrupts its interaction with PTPN23 and impairs MAPT/tau clearance, implicating dysfunction of this pathway in neurodegenerative pathogenesis. These findings establish microaggrephagy as a distinct cellular mechanism for degrading pathological protein aggregates, provide a molecular basis for its function, and suggest potential therapeutic targets for proteinopathies.