Different from canonical ubiquitin-like proteins, Hub
1
does not form covalent conjugates with substrates but binds proteins non-
covalently. In
Saccharomyces cerevisiae
, Hub
1
associates with spliceosomes and mediates alternative splicing of
SRC
1
, without
affecting pre-mRNA splicing generally. Human Hub
1
is highly similar to its yeast homolog, but its cellular function remains largely
unexplored. Here, we show that human Hub
1
binds to the spliceosomal protein Snu
66
as in yeast; however, unlike its
S. cerevisiae
homolog, human Hub
1
is essential for viability. Prolonged
in vivo
depletion of human Hub
1
leads to various cellular defects, including
splicing speckle abnormalities, partial nuclear retention of mRNAs, mitotic catastrophe, and consequently cell death by apoptosis.
Early consequences of Hub
1
depletion are severe splicing defects, however, only for specific splice sites leading to exon skipping
and intron retention. Thus, the ubiquitin-like protein Hub
1
is not a canonical spliceosomal factor needed generally for splicing, but
rather a modulator of spliceosome performance and facilitator of alternative splicing
