Secretion is a second fate for p62 and is coupled to KEAP1/NRF2 signaling
- 1Hirosaki University
Abstract
Cells degrade the autophagy receptor p62/sequestosome 1 (SQSTM1) in lysosomes. By knocking the HiBiT peptide into the endogenous SQSTM1 locus, we show that export is a second, quantitatively comparable fate. Specifically, p62 leaves cells continuously inside membrane-enclosed carriers at a rate similar to that of LC3B. Blocking lysosomal degradation amplifies release through an ATG5- and FIP200-dependent route, whereas a basal route persists in autophagy-deficient cells. Thus, p62 exits by at least two parallel pathways. Export requires PB1-mediated self-oligomerization but not LC3 binding, Kelch-like ECH-associated protein 1 (KEAP1) binding, or an intact ubiquitin-associated domain. Hence, oligomerization is the sorting determinant. KEAP1 is also released, and dominant-negative RAB27A retains both proteins inside cells and lowers nuclear factor erythroid 2-related factor 2 transcriptional output. Secretion is therefore a second outlet for the p62-KEAP1 module, and its interruption co-varies with a dampened oxidative stress response.
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BibTeX
@misc{saito2026secretion,
title = {{Secretion is a second fate for p62 and is coupled to KEAP1/NRF2 signaling}},
author = {K. Saito and T. Takahashi and M. Arakawa and E. Morita},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757498},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757498v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Secretion is a second fate for p62 and is coupled to KEAP1/NRF2 signaling
AU - K. Saito
AU - T. Takahashi
AU - M. Arakawa
AU - E. Morita
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757498
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757498v1
AB - Cells degrade the autophagy receptor p62/sequestosome 1 (SQSTM1) in lysosomes. By knocking the HiBiT peptide into the endogenous SQSTM1 locus, we show that export is a second, quantitatively comparable fate. Specifically, p62 leaves cells continuously inside membrane-enclosed carriers at a rate similar to that of LC3B. Blocking lysosomal degradation amplifies release through an ATG5- and FIP200-dependent route, whereas a basal route persists in autophagy-deficient cells. Thus, p62 exits by at least two parallel pathways. Export requires PB1-mediated self-oligomerization but not LC3 binding, Kelch-like ECH-associated protein 1 (KEAP1) binding, or an intact ubiquitin-associated domain. Hence, oligomerization is the sorting determinant. KEAP1 is also released, and dominant-negative RAB27A retains both proteins inside cells and lowers nuclear factor erythroid 2-related factor 2 transcriptional output. Secretion is therefore a second outlet for the p62-KEAP1 module, and its interruption co-varies with a dampened oxidative stress response.
ER -