p62/SQSTM1 selectively supports starvation-induced autophagy in N2a neuroblastoma cells

Marimuthu, A.; Saha, D.; Vengataraghavan, V.; Bangarupeta Murali, M. J.; Devanathan, V.

doi:10.64898/2026.01.03.697476

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bioRxiv · 10.64898/2026.01.03.697476

p62/SQSTM1 selectively supports starvation-induced autophagy in N2a neuroblastoma cells

Marimuthu, A.·Saha, D.·Vengataraghavan, V.·Bangarupeta Murali, M. J.·Devanathan, V.

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Abstract

Autophagy is a critical cellular process that maintains homeostasis and enables adaptation to metabolic stress. The selective autophagy receptor p62/SQSTM1 has been implicated in multiple aspects of autophagy regulation; however, its specific contribution to basal versus stress-induced autophagic flux remains incompletely defined, particularly in neuronal cells. In this study, we investigated the role of p62 in regulating basal and starvation-induced autophagy using a CRISPR-Cas9-generated p62 knockout (p62-/-) neuroblastoma (N2a) cell model. Autophagic flux was quantified by measuring LC3-II accumulation in the presence and absence of the lysosomal inhibitor bafilomycin A1. Under nutrient-replete conditions, basal autophagic flux was comparable between wild-type and p62-deficient cells, indicating that p62 is dispensable for constitutive autophagy. In contrast, starvation robustly increased autophagic flux in wild-type cells but failed to do so in p62-/- cells, demonstrating a requirement for p62 in starvation-induced autophagy. Consistent with a stress-responsive role, p62 protein levels increased during starvation in wild-type cells under lysosomal inhibition, reflecting enhanced p62 expression rather than impaired degradation. Together, these findings reveal a context-dependent function for p62 in neuronal autophagy, whereby p62 is essential for mounting an effective autophagic response to nutrient deprivation but is not required for basal autophagic turnover.

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Marimuthu, A., Saha, D., Vengataraghavan, V., Bangarupeta Murali, M. J., Devanathan, V.. 2026-01-03. p62/SQSTM1 selectively supports starvation-induced autophagy in N2a neuroblastoma cells. https://doi.org/10.64898/2026.01.03.697476

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