Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST
Creators
- Kraus, Felix
- He, Yuchen
- Swarup, Sharan
- Overmyer, Katherine A.
- Jiang, Yizhi
- Brenner, Johann
- Capitanio, Cristina
- Bieber, Anna
- Jen, Annie
- Nightingale, Nicole M.
- Anderson, Benton J.
- Lee, Chan
- Paulo, Joao A.
- Smith, Ian R.
- Plitzko, Jürgen M.
- Gygi, Steven P.
- Schulman, Brenda A.
- Wilfling, Florian
- Coon, Joshua J.
- Harper, J. Wade
Description
Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multi-omic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in NPC1-/- and NPC2-/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lyso-phosphatidylcholine species and multi-lamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS-complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2-/- cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs.
Files
uncroppedWB.pdf
Files
(47.0 MB)
| Name | Size | Download all |
|---|---|---|
|
md5:ad2a6435cbffc15f73547b45d1ec3a3d
|
7.8 kB | Download |
|
md5:301893bb97a81615f471b23409271ee1
|
1.2 kB | Download |
|
md5:2f5ffc6d7e6a0054d128a527a1b733a1
|
1.2 kB | Download |
|
md5:9b1f53c9e67e424769c0add704efeb7b
|
1.2 kB | Download |
|
md5:f19277c0c94d513839a2d13df9b5693a
|
1.2 kB | Download |
|
md5:e21b417f22ef6069a071498db2c89e2f
|
1.5 kB | Download |
|
md5:a8fb0a36e60a069237cca69dfa7a0e9f
|
1.5 kB | Download |
|
md5:cedd53e08366a9d08209a8ed43dadf78
|
1.5 kB | Download |
|
md5:0e93b7cdf4a9d58318ec5ec192444230
|
1.8 kB | Download |
|
md5:dff1ecad9d8bf15f5df264a4e1665c07
|
853 Bytes | Download |
|
md5:3e51a965ec98f96afe3f3bfdafbca11f
|
33.8 kB | Download |
|
md5:4c64c5634b5d690a2cb81cf063193537
|
27.8 kB | Download |
|
md5:bdd936ad94ec951ef2ee0205d29a9f22
|
32.5 kB | Download |
|
md5:1dfdd14206ada70a382cd5f58ec194b5
|
182.7 kB | Download |
|
md5:e65816cdea7d0250502d974c8b1a321d
|
2.2 kB | Download |
|
md5:f42579c8998d87fccac343f6495d1c12
|
31.8 kB | Download |
|
md5:0dc25a90ed8a2384d9183b76a9be87c8
|
27.6 kB | Download |
|
md5:13ae03c9eb1760f2c267ceab4131ec54
|
30.7 kB | Download |
|
md5:2f4785f00068e77fdc295be220589c74
|
31.7 kB | Download |
|
md5:92b88a98d000db8f25364f1fa62b3669
|
30.0 kB | Download |
|
md5:d326f0971d86c9e02c44cd5e2ffeb902
|
3.2 kB | Download |
|
md5:e06f88f75e93ede479d565f0f09f9c46
|
31.8 kB | Download |
|
md5:809bc9dfbc14b4e786434060d3f7401c
|
2.3 kB | Download |
|
md5:ba4edd5c664230265840c361530cc289
|
26.2 kB | Download |
|
md5:26dc5bdc7f025f62ff742604768e7b0c
|
4.1 kB | Download |
|
md5:845dca6d348a0c8ff216998979597dcc
|
16.5 kB | Download |
|
md5:c1a879ffb331454c3e1d50066d9f9a91
|
17.2 MB | Download |
|
md5:e11179aa33bb0ab54a72667adba9d2db
|
69.3 kB | Download |
|
md5:cf05c91215c0fe4eff2a60d3f810eb0d
|
5.9 MB | Download |
|
md5:9bf5886dc5f855b9872883e23d56db9b
|
15.0 MB | Download |
|
md5:2be81b734478d251a681ec4dc482afc1
|
8.1 MB | Download |
|
md5:b8b66ffb21b07862d54b5fe87589fca0
|
68.6 kB | Download |
|
md5:42e50cd4935e3a9fac6af2b64e677efb
|
195.4 kB | Preview Download |
Additional details
Related works
- Is supplement to
- Preprint: 10.1101/2024.03.26.586828 (DOI)