Sec22c has been characterized as an endoplasmic reticulum (ER)-localized transmembrane
protein involved in regulation of the vesicle transport between the ER and the Golgi.
Sec22c has several isoforms generated by alternative splicing that changes the number
of the C-terminal transmembrane domains (TMDs). However, the physiological significance
of the splicing remains unknown. Here we show that the splicing isoforms containing
four TMDs unexpectedly localized at cis-Golgi, whereas the splicing isoforms containing
less than four TMDs localized at the ER. The C-terminal fragment containing the four
TMDs was sufficient for the cis-Golgi localization and bound to ADP-ribosylation factor
4 (ARF4). ARF4 knockdown and overexpression of a constitutively active mutant of ARF4
decreased the cis-Golgi localization of the C-terminal fragment and the full-length
protein, respectively. These results indicate that the splicing-dependent changes
in the number of TMDs allow Sec22c to regulate the subcellular localization in cooperation
with ARF4, implying that Sec22c will function at the Golgi as well as the ER.