PT  - JOURNAL ARTICLE
AU  - Lakshya Bajaj
AU  - Alberto di Ronza
AU  - Pengcheng Zheng
AU  - Aiden Eblimit
AU  - Rituraj Pal
AU  - Jaiprakash Sharma
AU  - Dany Roman
AU  - John R. Collette
AU  - Richard N. Sifers
AU  - Sung Y. Jung
AU  - Rui Chen
AU  - Randy W. Schekman
AU  - Marco Sardiello
TI  - A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer
AID  - 10.1101/773804
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 773804
4099  - http://biorxiv.org/content/early/2019/09/18/773804.short
4100  - http://biorxiv.org/content/early/2019/09/18/773804.full
AB  - Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.