Lysosomes break down macromolecules, clear cellular waste and recycle nutrients such as cystine. We describe a novel mechanism whereby JIP4 regulates lysosomal cystine storage by controlling the abundance of cystinosin (CTNS), the transporter responsible for lysosomal cystine efflux. To this end, JIP4, previously characterized as a motor adaptor and kinase signaling scaffold, suppresses TMEM55B-dependent ubiquitylation of CTNS. Loss of JIP4 reduces CTNS protein levels, leading to lysosomal cystine accumulation and lysosomal storage defects that phenocopy loss of CTNS in both human cells and the renal proximal tubules of JIP4 knockout mice. These phenotypes mirror cystinosis, the lysosomal storage disease caused by CTNS loss-of-function. Our findings thus reveal a fundamental process that controls the efflux of lysosomal cystine and has relevance to understanding human disease arising from JIP4 mutations. ### Competing Interest Statement The authors have declared no competing interest. NIH, AG085824, AG062210, R35GM150619 Michael J. Fox Foundation, https://ror.org/03arq3225, ASAP-000580

A molecule designed to activate iron locked up in organelles called lysosomes and thereby induce cell death might offer a way to tackle treatment-resistant cancer.

Mutations in LRP10, a low-density lipoprotein receptor family member, cause familial Parkinson's disease and dementia with Lewy bodies. However, its direct cellular functions remain largely undefined....

Wang et al. show the recruitment of the lipid channel protein VPS13C and formation of VPS13C-dependent contacts between endoplasmic reticulum and lysosomes after lysosomal damage.

Wang et al. show the recruitment of the lipid channel protein VPS13C and formation of VPS13C-dependent contacts between endoplasmic reticulum and lysosomes after lysosomal damage.

As a scientist, starting from my postdoc and continuing in my own lab, we have helped redefine the role of the lysosome. Historically, it was considered a

A new study on a gene called VPS13C adds to growing evidence that lysosomal dysfunction may be one mechanism through which Parkinson’s disease arises.

Nature Cell Biology - Wang et al. show the recruitment of the lipid channel protein VPS13C and formation of VPS13C-dependent contacts between endoplasmic reticulum and lysosomes after lysosomal...

A growing body of research suggests that preventing the viral infection can help stave off cognitive decline.