JCI insightOct 23, 2026

The cell recycling receptor TEX264 helps skin cells mature and is disrupted in Darier disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 24, 2026

Abstract

Up-regulation of TEX264, a receptor associated with selective autophagy, is found in areas of premature cornification in patient biopsies.

Differentiating keratinocytes undergo a catabolic process that involves breaking down organelles and nuclei to form the epidermal barrier.
Live imaging revealed fragmentation of the endoplasmic reticulum and lysosomal engulfment in the cornifying layers of the epidermis.
Increased TEX264 expression was linked to endoplasmic reticulum stress and led to early cornification in organotypic epidermis.
Ectopic TEX264 in undifferentiated keratinocytes induced endoplasmic reticulum fragments, while in differentiated keratinocytes, it accelerated their elimination.
Knockout of TEX264 or inhibition of its activation disrupted the maturation of organotypic epidermal cultures.
Increased TEX264 was observed in areas of dyskeratosis in biopsies from patients with Darier disease, suggesting a role in cornification.

Simplified

Differentiating keratinocytes break down their organelles and nuclei to become the compacted cornified layers of the epidermal barrier in a poorly understood catabolic process. Live confocal imaging of stratified human organotypic epidermis revealed endoplasmic reticulum (ER) fragmentation and lysosomal engulfment in the cornifying layers, where we found up-regulation of TEX264, a receptor that mediates selective autophagy of the ER (reticulophagy). TEX264 expression was increased by ER stress, which caused precocious cornification of organotypic epidermis. In undifferentiated keratinocytes, ectopic TEX264 was sufficient to induce ER fragments, while in highly differentiated keratinocytes, it accelerated ER elimination and nuclear shrinkage; these effects were abolished by mutating the LC3 interacting region required for its autophagic function. Knockout of TEX264 or inhibiting its activation disrupted the maturation of organotypic cultures, pointing to a critical role for reticulophagy in cornification. Finally, in patient biopsies and an organotypic model of Darier disease, a genetic cornification disorder linked to ER dysfunction, we found increased TEX264 in areas of premature cornification (dyskeratosis). Our results identified TEX264 as a key driver of late-stage epidermal differentiation and led us to propose a model of cornification in which keratinocytes activate selective autophagy receptors to orchestrate orderly organelle elimination during cutaneous barrier formation.

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The cell recycling receptor TEX264 helps skin cells mature and is disrupted in Darier disease

Abstract

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