mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival

Abstract

Lysosomes are essential organelles that function to degrade and recycle unwanted, damaged and toxic biological components. Lysosomes also act as signalling platforms in activating the nutrient‐sensing kinase mTOR. mTOR regulates cellular growth, but it also helps to maintain lysosome identity by initiating lysosomal tubulation through a process termed autophagosome‐lysosome reformation (ALR). Here we identify a lysosomal pool of phosphatidylinositol 3‐phosphate that, when depleted by specific inhibition of the class III phosphoinositide 3‐kinase VPS34, results in prolonged lysosomal tubulation. This tubulation requires mTOR activity, and we identified two direct mTOR phosphorylation sites on UVRAG (S550 and S571) that activate VPS34. Loss of these phosphorylation sites reduced VPS34 lipid kinase activity and resulted in an increase in number and length of lysosomal tubules. In cells in which phosphorylation at these UVRAG sites is disrupted, the result of impaired lysosomal tubulation alongside ALR activation is massive cell death. Our data imply that ALR is critical for cell survival under nutrient stress and that VPS34 is an essential regulatory element in this process.

References 51

1. 1.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1093/jmcb/mjt022

2. 2.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1042/bj20071427

3. 3.
   Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase · 2014

   No notice
4. 4.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1083/jcb.201306041

5. 5.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1074/jbc.m507201200

6. 6.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1172/jci77598

7. 7.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1016/j.yexcr.2012.09.004

8. 8.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1073/pnas.0809136105

9. 9.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1038/nature05185

10. 10.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/35083076

11. 11.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.tcb.2010.03.002

12. 12.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1073/pnas.1305286110

13. 13.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1074/jbc.m900573200

14. 14.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1042/bj20090489

15. 15.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/s0022-5320(84)80024-6

16. 16.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.ajhg.2008.03.004

17. 17.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ncb2848

18. 18.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1091/mbc.e08-12-1248

19. 19.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1126/science.1199498

20. 20.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1091/mbc.e08-01-0080

21. 21.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/sj.embor.7401155

22. 22.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1091/mbc.e13-08-0447

23. 23.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1091/mbc.e08-12-1249

24. 24.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1371/journal.pgen.1004449

25. 25.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1126/science.1236566

26. 26.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1083/jcb.152.3.519

27. 27.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cell.2012.12.016

28. 28.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.molcel.2014.11.013

29. 29.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.4161/auto.19496

30. 30.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.4161/auto.6.7.13033

31. 31.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nrm2328

32. 32.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ncb1426

33. 33.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/emboj.2013.171

34. 34.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1074/jbc.273.7.3963

35. 35.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.12703/p6-52

36. 36.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1111/febs.12116

37. 37.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ncb2557

38. 38.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ncb2757

39. 39.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cell.2010.02.024

40. 40.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1083/jcb.201306140

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