TMEM55B Links Autophagy Flux, Lysosomal Repair, and TFE3 Activation in Response to Oxidative Stress

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jan 3

PMID 38168055

Authors

Eutteum Jeong

Rose Willett

Alberto Rissone

Martina La Spina

Rosa Puertollano

Affiliations

Soon will be listed here.

Abstract

Lysosomes have emerged as critical regulators of cellular homeostasis. Here we show that the lysosomal protein TMEM55B contributes to restore cellular homeostasis in response to oxidative stress by three different mechanisms: (1) TMEM55B mediates NEDD4-dependent PLEKHM1 ubiquitination, causing PLEKHM1 proteasomal degradation and halting autophagosome/lysosome fusion; (2) TMEM55B promotes recruitment of components of the ESCRT machinery to lysosomal membranes to stimulate lysosomal repair; and (3) TMEM55B sequesters the FLCN/FNIP complex to facilitate translocation of the transcription factor TFE3 to the nucleus, allowing expression of transcriptional programs that enable cellular adaptation to stress. Knockout of tmem55 genes in zebrafish embryos increases their susceptibility to oxidative stress, causing early death of tmem55-KO animals in response to arsenite toxicity. Altogether, our work identifies a role for TMEM55B as a molecular sensor that coordinates autophagosome degradation, lysosomal repair, and activation of stress responses.

References

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Li X, Rydzewski N, Hider A, Zhang X, Yang J, Wang W . A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol. 2016; 18(4):404-17. PMC: 4871318. DOI: 10.1038/ncb3324. View

Rawet-Slobodkin M, Elazar Z . PLEKHM1: a multiprotein adaptor for the endolysosomal system. Mol Cell. 2015; 57(1):1-3. DOI: 10.1016/j.molcel.2014.12.022. View

Barbaric I, Miller G, Dear T . Appearances can be deceiving: phenotypes of knockout mice. Brief Funct Genomic Proteomic. 2007; 6(2):91-103. DOI: 10.1093/bfgp/elm008. View

Attali I, Tobelaim W, Persaud A, Motamedchaboki K, Simpson-Lavy K, Mashahreh B . Ubiquitylation-dependent oligomerization regulates activity of Nedd4 ligases. EMBO J. 2017; 36(4):425-440. PMC: 5437815. DOI: 10.15252/embj.201694314. View

Carrington B, Varshney G, Burgess S, Sood R . CRISPR-STAT: an easy and reliable PCR-based method to evaluate target-specific sgRNA activity. Nucleic Acids Res. 2015; 43(22):e157. PMC: 4678847. DOI: 10.1093/nar/gkv802. View

Pu J, Guardia C, Keren-Kaplan T, Bonifacino J . Mechanisms and functions of lysosome positioning. J Cell Sci. 2016; 129(23):4329-4339. PMC: 5201012. DOI: 10.1242/jcs.196287. View

Saftig P, Puertollano R . How Lysosomes Sense, Integrate, and Cope with Stress. Trends Biochem Sci. 2020; 46(2):97-112. PMC: 7855039. DOI: 10.1016/j.tibs.2020.09.004. View

Raben N, Puertollano R . TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress. Annu Rev Cell Dev Biol. 2016; 32:255-278. PMC: 6490169. DOI: 10.1146/annurev-cellbio-111315-125407. View

10.

Radulovic M, Schink K, Wenzel E, Nahse V, Bongiovanni A, Lafont F . ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 2018; 37(21). PMC: 6213280. DOI: 10.15252/embj.201899753. View

11.

Keren-Kaplan T, Saric A, Ghosh S, Williamson C, Jia R, Li Y . RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin. Nat Commun. 2022; 13(1):1506. PMC: 8938451. DOI: 10.1038/s41467-022-28952-y. View

12.

Luzio J, Pryor P, Bright N . Lysosomes: fusion and function. Nat Rev Mol Cell Biol. 2007; 8(8):622-32. DOI: 10.1038/nrm2217. View

13.

McEwan D, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D . PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell. 2014; 57(1):39-54. DOI: 10.1016/j.molcel.2014.11.006. View

14.

Rotin D, Kumar S . Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol. 2009; 10(6):398-409. DOI: 10.1038/nrm2690. View

15.

Papadopoulos C, Kravic B, Meyer H . Repair or Lysophagy: Dealing with Damaged Lysosomes. J Mol Biol. 2019; 432(1):231-239. DOI: 10.1016/j.jmb.2019.08.010. View

16.

Lee I, Dinudom A, Sanchez-Perez A, Kumar S, Cook D . Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 2007; 282(41):29866-73. DOI: 10.1074/jbc.M701923200. View

17.

Kang Y, Li Y, Zhang T, Chi Y, Liu M . Effects of transcription factor EB on oxidative stress and apoptosis induced by high glucose in podocytes. Int J Mol Med. 2019; 44(2):447-456. PMC: 6605469. DOI: 10.3892/ijmm.2019.4209. View

18.

Goodwin J, Walkup 4th W, Hooper K, Li T, Kishi-Itakura C, Ng A . GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. Sci Adv. 2021; 7(40):eabj2485. PMC: 10938568. DOI: 10.1126/sciadv.abj2485. View

19.

Willett R, Martina J, Zewe J, Wills R, Hammond G, Puertollano R . TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat Commun. 2017; 8(1):1580. PMC: 5691037. DOI: 10.1038/s41467-017-01871-z. View

20.

Napolitano G, Di Malta C, Esposito A, de Araujo M, Pece S, Bertalot G . A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020; 585(7826):597-602. PMC: 7610377. DOI: 10.1038/s41586-020-2444-0. View