TMEM192 is a calcineurin-regulated membrane receptor for ubiquitin-independent lysophagy.

TMEM192 is a calcineurin-regulated lysosomal membrane receptor that enables ubiquitin-independent lysophagy by dephosphorylating Ser229 after lysosomal calcium efflux.

• Why it matters: Existing lysophagy models emphasize ubiquitin-dependent mechanisms, leaving how lysosomes are cleared when ubiquitination or adaptors are absent unclear.
• What they did: Cells were tested under conditions blocking protein ubiquitination or deleting autophagy adaptors, and lysosomal damage was used to trigger calcium efflux that activates calcineurin and dephosphorylates TMEM192 at Ser229.
• The result: Lysophagy persisted despite ubiquitination inhibition or adaptor deletion, while TMEM192 depletion or blocking Ser229 dephosphorylation severely impaired lysophagy and increased damaged lysosome accumulation, and TMEM192 deficiency worsened renal tubular injury in a mouse model of acute hyperuricemic nephropathy.

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