ATPase activity of DFCP1 controls selective autophagy

Viola Nähse (), Camilla Raiborg, Kia Wee Tan, Sissel Mørk, Maria Lyngaas Torgersen, Eva Maria Wenzel, Mireia Nager, Veijo T. Salo, Terje Johansen, Elina Ikonen, Kay Oliver Schink () and Harald Stenmark ()
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Viola Nähse: University of Oslo
Camilla Raiborg: University of Oslo
Kia Wee Tan: University of Oslo
Sissel Mørk: University of Oslo
Maria Lyngaas Torgersen: University of Oslo
Eva Maria Wenzel: University of Oslo
Mireia Nager: University of Tromsø, The Arctic University of Norway
Veijo T. Salo: University of Helsinki
Elina Ikonen: University of Helsinki
Kay Oliver Schink: University of Oslo
Harald Stenmark: University of Oslo

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) known as omegasomes, which are characterized by the presence of the ER protein DFCP1/ZFYVE1. The function of DFCP1 is unknown, as are the mechanisms of omegasome formation and constriction. Here, we demonstrate that DFCP1 is an ATPase that is activated by membrane binding and dimerizes in an ATP-dependent fashion. Whereas depletion of DFCP1 has a minor effect on bulk autophagic flux, DFCP1 is required to maintain the autophagic flux of p62 under both fed and starved conditions, and this is dependent on its ability to bind and hydrolyse ATP. While DFCP1 mutants defective in ATP binding or hydrolysis localize to forming omegasomes, these omegasomes fail to constrict properly in a size-dependent manner. Consequently, the release of nascent autophagosomes from large omegasomes is markedly delayed. While knockout of DFCP1 does not affect bulk autophagy, it inhibits selective autophagy, including aggrephagy, mitophagy and micronucleophagy. We conclude that DFCP1 mediates ATPase-driven constriction of large omegasomes to release autophagosomes for selective autophagy.

Date: 2023
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DOI: 10.1038/s41467-023-39641-9

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