Abstract:
:Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Nakamura S,Shigeyama S,Minami S,Shima T,Akayama S,Matsuda T,Esposito A,Napolitano G,Kuma A,Namba-Hamano T,Nakamura J,Yamamoto K,Sasai M,Tokumura A,Miyamoto M,Oe Y,Fujita T,Terawaki S,Takahashi A,Hamasaki M,Yamamotdoi
10.1038/s41556-020-00583-9subject
Has Abstractpub_date
2020-10-01 00:00:00pages
1252-1263issue
10eissn
1465-7392issn
1476-4679pii
10.1038/s41556-020-00583-9journal_volume
22pub_type
杂志文章abstract::Store-operated Ca(2+) channels (SOCs) are activated in response to Ca(2+) release from the endoplasmic reticulum (ER). The stromal interaction molecule 1 (STIM1) is the ER sensor that transmits the stored Ca(2+) content to the pore-forming SOCs Orai and TRPC channels. Recent studies reveal high levels of Orai1 and STI...
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更新日期:2016-07-01 00:00:00
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更新日期:2007-12-01 00:00:00
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