SARAF is an ER membrane protein, that inactivates store operated calcium entry (SOCE). ALG-2 regulates SARAF expression by modulating E3 ligases that are known to target SARAF. Although SARAF and ALG-2 are expressed in the heart, their pathophysiological role remains unknown. Here, we found that SARAF protein expression level was significantly decreased due to its polyubiquitination in cardiomyocytes excised from dilated cardiomyopathy (DCM) mice compared to control mice. The ALG-2 expression level was also significantly decreased in cardiomyocytes excised from DCM mice compared to control mice. We next observed that the expression level of both SARAF and ALG-2 are significantly decreased in ER stress-exposed HEK293 cells. Furthermore, we observed that knockdown of alg-2 decreased SARAF expression level in HEK293 cells. These data indicate that SARAF is degraded via ALG-2-mediated polyubiquitination under the ER stress condition in failing hearts. Further work is necessary to determine whether SARAF and/or ALG-2 can regulate cardiac function in DCM especially through in ER stress conditions.